Repeat resection in recurrent glioblastoma (3rGBM) Trial: A randomized care trial.

BACKGROUND: The prognosis for patients with recurrent glioblastoma (GBM) is dismal, and the question of repeat surgery at time of recurrence is common. Re-operation in the management of these patients remains controversial, as there is no randomized evidence of benefit. An all-inclusive pragmatic care trial is needed to evaluate the role of repeat resection. METHODS: 3rGBM is a multicenter, pragmatic, prospective, parallel-group randomized care trial, with 1:1 allocation to repeat resection or standard care with no repeat resection. To test the hypothesis that repeat resection can improve overall survival by at least 3 months (from 6 to 9 months), 250 adult patients with prior resection of pathology-proven glioblastoma for whom the attending surgeon believes repeat resection may improve quality survival will be enrolled. A surrogate measure of quality of life, the number of days outside of hospital/nursing/palliative care facility, will also be compared. Centers are invited to participate without financial compensation and without contracts. Clinicians may apply to local authorities to approve an investigator-led in-house trial, using a common protocol, web-based randomization platform, and simple standardized case report forms. DISCUSSION: The 3rGBM trial is a modern transparent care research framework with no additional risks, tests, or visits other than what patients would encounter in normal care. The burden of proof remains on repeat surgical management of recurrent GBM, because this management has yet to be shown beneficial. The trial is designed to help patients and surgeons manage the uncertainty regarding optimal care. CLINICAL TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov. Unique identifier: NCT04838782.

Rare cancers in Canada, 2006-2016: A population-based surveillance report and comparison of different methods for classifying rare cancers.

BACKGROUND: The cumulative burden from rare cancers has not been adequately explored in Canada. This analysis aims to characterize the occurrence of rare cancers among Canadians and estimate the probability of being diagnosed with a rare cancer among cancer patients with different demographic characteristics. METHODS: The Canadian Cancer Registry was used for this analysis. Cancer types were classified in three ways: using the SEER site recode scheme; by histology group; and by site/histology group. The age-standardized incidence rate (ASIR) and 95 % confidence intervals (CI) for each cancer type was estimated for diagnoses from 2006 to 2016. Two ASIR thresholds were used to classify cancers as rare:6/100,000/year and 15/100,000/year. Log-binomial regression was used to estimate the adjusted probability of having a rare cancer among those with cancer by age, sex and geographic region. RESULTS: Using the 6/100,000/year threshold, the incidence proportion (IP) of rare cancers ranged from 9.7 %(95 %CI:9.6,9.7 %)-17.0 %(95 %CI:16.9,17.0 %), and ranged from 19.2 %(95 %CI:19.1,19.3 %)-52.5 %(95 %CI:52.0,53.0 %) using the <15/100,000/year threshold. The adjusted probability of being diagnosed with a rare cancer was highest among those aged ≤19 years. There was higher concordance in estimates of the burden of rare cancers across methods to classify cancer types when the lower incidence rate threshold was used to define rare cancers. INTERPRETATION: This analysis yielded evidence that rare cancers comprise a substantial proportion of annual cancer diagnoses among Canadians. Findings from this analysis point to using a lower incidence rate threshold, to generate estimates of the burden of rare cancers that are robust to different cancer classification schemes.

Brain cancer survival in Canada 1996-2008: effects of sociodemographic characteristics.

Background: Literature suggests that factors such as rural residence and low socioeconomic status (ses) might contribute to disparities in survival for Canadian cancer patients because of inequities in access to care. However, evidence specific to brain cancer is limited. The present research estimates the effects of rural or urban residence and ses on survival for Canadian patients diagnosed with brain cancer. Methods: Adults diagnosed with primary malignant brain tumours during 1996-2008 were identified through the Canadian Cancer Registry. Brain tumours were classified using International Classification of Diseases for Oncology (3rd edition) site and histology codes. Hazard ratios (hrs) and 95% confidence intervals (cis) were estimated using Cox proportional hazards models. Events were restricted to individuals whose underlying cause of death was cancer-related. Postal codes were used to match patient records with Statistics Canada data for rural or urban residence and neighbourhood income as a surrogate measure of ses. Results: Of 25,700 patients included in the analysis, 78% died during the study period, 21% lived in rural areas, and 19% were in the lowest income group. A modest variation in survival by rural compared with urban residence was observed for patients with glioblastoma (first 5 weeks after diagnosis hr: 0.86; 95% ci: 0.79 to 0.99) and oligoastrocytoma (first 3 years after diagnosis hr: 1.41; 95% ci: 1.03 to 1.93). Small effects of low compared with high income were seen for patients with glioblastoma (first 1.5 years after diagnosis hr: 1.15; 95% ci: 1.08 to 1.22) and diffuse astrocytoma (first 6 months after diagnosis hr: 1.17; 95% ci: 1.00 to 1.36). Conclusions: Our analysis did not yield evidence of strong effects of rural compared with urban residence or ses strata on survival in brain cancer. However, some variation in survival for patients with specific histologies warrants further research into the mechanisms by which rural or urban residence and income stratum influences survival.

Conditional survival after a diagnosis of malignant brain tumour in Canada: 2000-2008.

BACKGROUND: "Conditional survival probability" is defined as the probability that a patient will survive an additional time, given that the patient has already survived a defined period of time after diagnosis. Such estimates might be more relevant for clinicians and patients during post-diagnosis care, because survival probability projections are based on the patient's survival to date. Here, we provides the first population-based estimates of conditional survival probabilities by histology for brain cancer in Canada. METHODS: Canadian Cancer Registry data were accessed for patients diagnosed with primary brain cancers during 2000-2008. Kaplan-Meier survival probabilities were estimated by histology. Conditional survival probabilities at 6 months (short-term, denoted scs) and 2 years (long-term, denoted lcs) were derived from the Kaplan-Meier survival estimates for a range of time periods. RESULTS: Among the 20,875 patients who met the study criteria, scs increased by a margin of 16-18 percentage points from 6-month survivors to 2-year survivors for the three most aggressive brain cancers. The lcs for 2-year survivors was 66% or greater for all tumour groups except glioblastoma. The lcs for 4-year survivors was 62% or greater for all histologies. For glioblastoma and diffuse astrocytoma, the lcs increased each year after diagnosis. For all other histologies, the lcs first increased and then plateaued from 2 years after diagnosis. The lcs and scs both worsened with increasing older age at diagnosis. SUMMARY: We report histologically specific conditional survival probabilities that can have value for clinicians practicing in Canada as they plan the course of follow-up for individual patients with brain cancer.

Solid Cancer Incidence in the Techa River Incidence Cohort: 1956-2007.

Previously reported studies of the Techa River Cohort have established associations between radiation dose and the occurrence of solid cancers and leukemia (non-CLL) that appear to be linear in dose response. These analyses include 17,435 cohort members alive and not known to have had cancer prior to January 1, 1956 who lived in areas near the river or Chelyabinsk City at some time between 1956 and the end of 2007, utilized individualized dose estimates computed using the Techa River Dosimetry System 2009 and included five more years of follow-up. The median and mean dose estimates based on these doses are consistently higher than those based on earlier Techa River Dosimetry System 2000 dose estimates. This article includes new site-specific cancer risk estimates and risk estimates adjusted for available information on smoking. There is a statistically significant (P = 0.02) linear trend in the smoking-adjusted all-solid cancer incidence risks with an excess relative risk (ERR) after exposure to 100 mGy of 0.077 with a 95% confidence interval of 0.013-0.15. Examination of site-specific risks revealed statistically significant radiation dose effects only for cancers of the esophagus and uterus with an ERR per 100 mGy estimates in excess of 0.10. Esophageal cancer risk estimates were modified by ethnicity and sex, but not smoking. While the solid cancer rates are attenuated when esophageal cancer is removed (ERR = 0.063 per 100 mGy), a dose-response relationship is present and it remains likely that radiation exposure has increased the risks for most solid cancers in the cohort despite the lack of power to detect statistically significant risks for specific sites.

Leukaemia incidence in the Techa River Cohort: 1953-2007.

BACKGROUND: Little is known about leukaemia risk following chronic radiation exposures at low dose rates. The Techa River Cohort of individuals residing in riverside villages between 1950 and 1961 when releases from the Mayak plutonium production complex contaminated the river allows quantification of leukaemia risks associated with chronic low-dose-rate internal and external exposures. METHODS: Excess relative risk models described the dose-response relationship between radiation dose on the basis of updated dose estimates and the incidence of haematological malignancies ascertained between 1953 and 2007 among 28 223 cohort members, adjusted for attained age, sex, and other factors. RESULTS: Almost half of the 72 leukaemia cases (excluding chronic lymphocytic leukaemia (CLL)) were estimated to be associated with radiation exposure. These data are consistent with a linear dose response with no evidence of modification. The excess relative risk estimate was 0.22 per 100 mGy. There was no evidence of significant dose effect for CLL or other haematopoietic malignancies. CONCLUSION: These analyses demonstrate that radiation exposures, similar to those received by populations exposed as a consequence of nuclear accidents, are associated with long-term dose-related increases in leukaemia risks. Using updated dose estimates, the leukaemia risk per unit dose is about half of that based on previous dosimetry.

Risk of renal cell carcinoma in relation to blood telomere length in a population-based case-control study.

BACKGROUND: There are few known risk factors for renal cell carcinoma (RCC). Two small hospital-based case-control studies suggested an association between short blood telomere length (TL) and increased RCC risk. METHODS: We conducted a large population-based case-control study in two metropolitan regions of the United States comparing relative TL in DNA derived from peripheral blood samples from 891 RCC cases and 894 controls. Odds ratios and 95% confidence intervals were estimated using unconditional logistic regression in both unadjusted and adjusted models. RESULTS: Median TL was 0.85 for both cases and controls (P=0.40), and no differences in RCC risk by quartiles of TL were observed. Results of analyses stratified by age, sex, race, tumour stage, and time from RCC diagnosis to blood collection were similarly null. In multivariate analyses among controls, increasing age and history of hypertension were associated with shorter TL (P<0.001 and P=0.07, respectively), and African Americans had longer TL than Caucasians (P<0.001). CONCLUSION: These data do not support the hypothesis that blood TL is associated with RCC. This population-based case-control study is, to our knowledge, the largest investigation to date of TL and RCC.

Meat-cooking mutagens and risk of renal cell carcinoma.

BACKGROUND: High-temperature cooked meat contains two families of carcinogens, heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). Given the kidneys' role in metabolism and urinary excretion of these compounds, we investigated meat-derived mutagens, as well as meat intake and cooking methods, in a population-based case-control study conducted in metropolitan Detroit and Chicago. METHODS: Newly diagnosed, histologically confirmed adenocarcinoma of the renal parenchyma (renal cell carcinoma (RCC)) cases (n=1192) were frequency matched on age, sex, and race to controls (n=1175). The interviewer-administered Diet History Questionnaire (DHQ) included queries for meat-cooking methods and doneness with photographic aids. Levels of meat mutagens were estimated using the DHQ in conjunction with the CHARRED database. RESULTS: The risk of RCC increased with intake of barbecued meat (P(trend)=0.04) and the PAH, benzo(a)pyrene (BaP) (multivariable-adjusted odds ratio and 95% confidence interval, highest vs lowest quartile: 1.50 (1.14, 1.95), P(trend)=0.001). With increasing BaP intake, the risk of RCC was more than twofold in African Americans and current smokers (P(interaction)<0.05). We found no association for HCAs or overall meat intake. CONCLUSION: BaP intake, a PAH in barbecued meat, was positively associated with RCC. These biologically plausible findings advocate further epidemiological investigation into dietary intake of BaP and risk of RCC.

How much can we say about site-specific cancer radiation risks?

Studies of Mayak workers and people who lived along the Techa River have demonstrated significant associations between low-dose-rate radiation exposure and increased solid cancer risk. It is of interest to use the long-term follow-up data from these cohorts to describe radiation effects for specific types of cancer; however, statistical variability in the site-specific risk estimates is large. The goal of this work is to describe this variability and provide Bayesian adjusted risk estimates. We assume that the site-specific estimates can be viewed as a sample from some underlying distribution and use Bayesian methods to produce adjusted excess relative risk per gray estimates in the Mayak and Techa River cohorts. The impact of the adjustment is compared to that seen in similar analyses in the atomic bomb survivors. Site-specific risk estimates in the Mayak and Techa River cohorts have large uncertainties. Unadjusted estimates vary from implausibly large decreases to large increases, with a range that greatly exceeds that found in the A-bomb survivors. The Bayesian adjustment markedly reduced the range of the site-specific estimates for the Techa River and Mayak studies. The extreme variability in the site-specific risk estimates is largely a consequence of the small number of excess cases. The adjusted estimates provide a useful perspective on variation in the actual risks. However, additional work on interpretation of the adjusted estimates, extension of the methods used in describing effect modification, and making more use of prior knowledge is needed to make these methods useful.

Family history of cancer and renal cell cancer risk in Caucasians and African Americans.

BACKGROUND: The association between renal cell carcinoma (RCC) risk and family history of cancer has not been examined with an adequate number of African Americans (AAs). METHODS: In a population-based case-control study, unconditional logistic regression was used to calculate the association between RCC risk and a family history of cancer among 1217 RCC cases and 1235 controls. RESULTS: Increased RCC risk was shown for subjects with at least one first-degree relative with kidney cancer (odds ratio=2.29; 95% confidence interval=1.31-4.00). No differences in risk were observed when analyses were stratified by race. For Caucasians, excess risk was observed among those reporting a sibling with kidney cancer, whereas for AAs, increased risk occurred among subjects reporting either a sibling or parent affected with the disease. A family history of non-renal cancers, and those related to smoking or to the von Hippel-Lindau syndrome, revealed no association with RCC risk. CONCLUSION: The RCC risk associated with a family history of kidney cancer is similar among Caucasians and AAs.

Breast cancer incidence following low-dose rate environmental exposure: Techa River Cohort, 1956-2004.

In the 1950s, the Mayak nuclear weapons facility in Russia discharged liquid radioactive wastes into the Techa River causing exposure of riverside residents to protracted low-to-moderate doses of radiation. Almost 10,000 women received estimated doses to the stomach of up to 0.47 Gray (Gy) (mean dose=0.04 Gy) from external gamma-exposure and (137)Cs incorporation. We have been following this population for cancer incidence and mortality and as in the general Russian population, we found a significant temporal trend of breast cancer incidence. A significant linear radiation dose-response relationship was observed (P=0.01) with an estimated excess relative risk per Gray (ERR/Gy) of 5.00 (95% confidence interval (CI), 0.80, 12.76). We estimated that approximately 12% of the 109 observed cases could be attributed to radiation.

Trends in incidence of primary brain tumors in the United States, 1985-1994.

Brain tumor incidence has increased over the last 20 years in all age groups, both overall and for specific histologies. Reasons attributed to these increases include increase in lymphoma due to HIV/AIDS, introduction of computed tomography/magnetic resonance imaging, and changes in coding/classification. The purpose of this study was to describe overall and histologic-specific incidence trends in a population-based series of primary benign and malignant brain tumors. Data from the Central Brain Tumor Registry of the United States from 1985 through 1994 were used to determine incidence trends in the broad age groups 0-19, 20-64, and > or = 65 years, both overall and for selected histologies. Poisson regression was used to express trends as average annual percentage change. Overall, incidence increased modestly (annual percentage change 0.9%, 95% confidence interval, 0.4, 1.4). When lymphomas were excluded, this result was not statistically significant (annual percentage change 0.5%, 95% confidence interval, -0.1, 1.1). Specific histologies that were increasing were lymphomas in individuals aged 20 to 64 years and in males aged 65 years or older, ependymomas in the population aged 20 to 64 years, nerve sheath tumors in males, and pituitary tumors in females. Increases that were not specific to any population subgroup were seen for glioblastoma, oligodendrogliomas, and astrocytomas, excluding not otherwise specified (NOS) tumors. Corresponding decreases were noted for NOS, astrocytoma NOS, and glioma NOS. Increasing incidence trends for lymphomas were consistent with previous literature. Improvements in diagnostic technology in addition to changes in classification and coding were likely to be responsible for decreases seen in incidence of NOS subgroups and corresponding increases in glioma subgroups. In contrast, the increases identified for ependymomas, nerve sheath tumors, and pituitary tumors were less likely to be artifacts of improvements in diagnosis, and they warrant further study.

Prevalence estimates for primary brain tumors in the United States by behavior and major histology groups.

Prevalence rates are used to supplement descriptions of disease and are unavailable for all primary brain tumors in the United States. Data from two population-based tumor registries were obtained from the Central Brain Tumor Registry of the United States and used to compute age-specific incidence rates (1985-1994) and survival curves for further use in a statistical model to estimate prevalence rates. Prevalence rates were then used to estimate the number of individuals living with a brain tumor diagnosis in the U.S. population for the year 2000. The overall incidence rate in these regions is 13.8 per 100,000 with 2-, 5-, and 10-year survival rates of 58%, 49%, and 38%, respectively. The prevalence rate for all primary brain tumors is 130.8 per 100,000 with approximately 350,000 individuals estimated to be living with this diagnosis in the United States in 2000. The prevalence rate for malignant tumors, 29.5 per 100,000, is similar to previous reports. The prevalence rate for benign tumors, 97.5 per 100,000, is new. Unlike incidence data, the proportion (and expected number) of existing benign tumors (75%, 267,000) is considerably greater than that for malignant tumors (23%, 81,000), reflecting the better prognosis of benign tumors diagnosed in individuals younger than 60 years old. These data underscore the impact of primary brain tumors in the U.S. health care system and emphasize the need for quality-of-life considerations, particularly for those long-term survivors of benign tumors.

Current epidemiological trends and surveillance issues in brain tumors.

The absence of an overall increase in incidence rates for all primary brain tumors since the 1950s argues against a recently introduced environmental tumorigen impacting these tumors. Historical increases in brain cancer mortality and incidence rates appear to be leveling off following the widespread introduction of CT and MRI scans, indicating that increases in overall rates of malignant tumors are likely to be an artifact of diagnosis and reporting issues. Further studies are needed to understand those tumor types with rates that do appear to be increasing among adults; specifically lymphomas, nerve sheath tumors, pituitary tumors and ependymomas. Patterns of incidence by race, ethnicity, socioeconomic status, and seasonal and regional variation would assist in directing relevant new research questions. Filling in the gap of information on patterns for prevalent, second primaries and metastatic tumors may be useful in understanding the public perception regarding brain tumor rates and would be a valuable addition to healthcare planning tools.

Epidemiology of brain tumors.

Primary brain tumor incidence and survival patterns are emerging, assisted by progress in molecular classification. Evidence is accumulating to suggest that infectious diseases may affect the risk of developing a brain tumor, although data require clarification. Other promising research directions include evaluating the role of diet and allergic conditions in reducing brain tumor risk.

The descriptive epidemiology of brain tumors.

Brain tumors have been the subject of controversy both with respect to patterns of occurrence and to potential causes. This article provides a description of current data resources on brain tumors and outlines issues affecting the interpretation of population-based data. A template for estimating regional expected values for brain tumors is provided, and current patterns of incidence, survival, and conditional survival are described. The occurrence of second primary tumors and quality of life studies are also reviewed.

The contribution of nonmalignant tumors to CNS tumor incidence rates among children in the United States.

OBJECTIVES: According the U.S. National Cancer Institute (NCI), the incidence rate of primary malignant central nervous system (CNS) neoplasms among children is about 30 per million person-years. This rate, however, underestimates the true burden of CNS tumors because nonmalignancies are not included in the NCI case reporting system. Intracranial tumors, to an extent regardless of their histological behavior, can have a malignant clinical course and result in a high degree of morbidity and mortality. The purpose of this report is to estimate the contribution that nonmalignant tumors have on the overall incidence of CNS tumors in children. METHODS: Population-based data from the Central Brain Tumor Registry of the United States were analyzed. Included in the analysis were children aged 0-19 years who were diagnosed with a primary CNS tumor from 1990-93 (N = 1133). RESULTS: The inclusion of nonmalignancies increased the CNS tumor incidence rate by 28% from 29.4 to 37.6 per million person-years. The increases were 17% for children aged 0-4 years, 17% for children aged 5-9 years, 31% for children aged 10-14 years and 57% for adolescents aged 15-19 years. Differences in patterns between malignant and nonmalignant tumor occurrence by sex, histology, and location were also observed. CONCLUSION: Because of the potentially profound adverse health effects on children who experience CNS tumors, the systematic collection of both malignancies and nonmalignancies is consistent with the mission of public health surveillance. Without such population-based data, analytic epidemiologic studies to evaluate disease etiology and assess disease consequences are greatly hindered.

The conditional probability of survival of patients with primary malignant brain tumors: surveillance, epidemiology, and end results (SEER) data.

BACKGROUND: Five-year survival estimates in standard cancer reports provide a general description of disease outcome that is useful for surveillance and comparison purposes. However, for cancer survivors these overall survival rates may be discouraging, and the relevant question regarding an individual is this: Once he or she has survived for a specified period of time, what is the probability of survival over the next period of time? METHODS: To address this, conditional survival rates by histology for malignant brain tumor survivors were estimated using the SEER public use data and the Portable Survival System, with 19,105 brain and other nervous system patients diagnosed between 1979 and 1993. Given that the survival curve declines more rapidly in the first 2 years than in subsequent years, conditional probabilities of surviving 5 years given survival to 2 years and 95% confidence intervals (CIs)were calculated. As age is a strong prognostic factor for these tumors, conditional probabilities were also estimated by categories of age. RESULTS: Estimated 2- and 5-year relative survival rates for patients with malignant brain and other CNS tumors were 36.2% and 27.6%; however, the conditional probability of surviving to 5 years, given survival to 2 years, reaches 76.2% (95% CI: 74.8-77.6). Conditional probabilities varied by histology and age at diagnosis. The conditional probability of surviving 5 years after surviving 2 years was 67.8% (95% CI: 62.6-73.1) for patients with anaplastic astrocytomas, 36.4% (95% CI: 31.9-41.6) for patients with glioblastomas, and 79.8% (95% CI:75.3-84.1) for patients with medulloblastomas. CONCLUSIONS: Conditional probabilities provide important and encouraging information for those who are brain tumor survivors. The utility of these estimates for other time intervals and other cancers or diseases should be considered.

Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990-1994.

The Central Brain Tumor Registry of the United States (CBTRUS) obtained 5 years of incidence data (1990-1994)--including reports on all primary brain and CNS tumors--from 11 collaborating state cancer registries. Data were available for 20,765 tumors located in the brain, meninges, and other CNS sites, including the pituitary and pineal glands. The average annual incidence was estimated at 11.5 cases per 100,000 person-years. The higher incidence of tumors in male patients (12.1 per 100,000 person-years) than in female patients (11.0 per 100,000 person-years) was statistically significant (P < 0.05); the higher incidence in whites (11.6 per 100,000 person-years) compared with blacks (7.8 per 100,000 person-years) was statistically significant (P < 0.05). The most frequently reported histologies were meningiomas (24.0%) and glioblastomas (22.6%). Higher rates for glioblastomas, anaplastic astrocytomas, oligodendrogliomas, anaplastic oligodendrogliomas, ependymomas, mixed gliomas, astrocytomas not otherwise specified, medulloblastomas, lymphomas, and germ cell tumors in male than in female patients were statistically significant (P < 0.05), with relative risks (RR) ranging from 1.3 to 3.4. Meningiomas were the only tumors with a significant excess in females (RR = 0.5). We noted higher occurrence rates in whites than in blacks for the following histologies: diffuse astrocytomas, anaplastic astrocytomas, glioblastomas, oligodendrogliomas, ependymomas, mixed gliomas, astrocytomas NOS, medulloblastomas, nerve sheath tumors, hemangioblastomas, and germ cell tumors, with RRs ranging from 1.5 to 3.4. Racial differences in occurrence rates were not observed for predominately benign meningiomas or pituitary tumors. This study represents the largest compilation of data on primary brain and CNS tumors in the United States. Standard reporting definitions and practices must be universally adopted to improve the quality and use of cancer registry data.