Ann W. Hsing

International trends and patterns of prostate cancer incidence and mortality

Prostate cancer is the most commonly diagnosed cancer in western men, and incidence is rising rapidly in most countries, including low‐risk populations. Age‐adjusted incidence and mortality rates from 15 and 13 countries between 1973–77 and 1988–92, respectively, were compared to provide leads for future analytic studies. Large increases in both incidence and mortality rates of prostate cancer were seen for all countries. For incidence, increases were more pronounced in the United States, Canada, Australia, France and the Asian countries, while the increases in medium‐risk countries were moderate. Increases in incidence ranged from 25%–114%, 24%–55% and 15%–104% in high‐, medium‐ and low‐risk countries, respectively. Mortality rates rose more rapidly in Asian countries than in high‐risk countries. Substantial differences in incidence and mortality across countries were evident, with U.S. blacks having rates that were 50–60 times higher than the rates in Shanghai, China. Increasing incidence rates in the United States and Canada are likely to be due in part to the widespread use of transurethral resection of the prostate and prostate‐specific antigen testing, while increases in the Asian countries are probably related to westernization in these low‐risk populations. The large disparities in incidence between high‐ and low‐risk countries may be due to a combination of genetic and environmental factors. Future studies are needed to examine gene‐gene and gene‐environment interactions in various countries concurrently to shed light on the etiology of prostate cancer and to help elucidate reasons for the large differences in risk between populations. Int. J. Cancer 85:60–67, 2000.

Prostate Cancer Screening in the Randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: Mortality Results after 13 Years of Follow-up

BACKGROUND The prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was undertaken to determine whether there is a reduction in prostate cancer mortality from screening using serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE). Mortality after 7-10 years of follow-up has been reported previously. We report extended follow-up to 13 years after the trial. METHODS A total of 76 685 men, aged 55-74 years, were enrolled at 10 screening centers between November 1993 and July 2001 and randomly assigned to the intervention (organized screening of annual PSA testing for 6 years and annual DRE for 4 years; 38 340 men) and control (usual care, which sometimes included opportunistic screening; 38 345 men) arms. Screening was completed in October 2006. All incident prostate cancers and deaths from prostate cancer through 13 years of follow-up or through December 31, 2009, were ascertained. Relative risks (RRs) were estimated as the ratio of observed rates in the intervention and control arms, and 95% confidence intervals (CIs) were calculated assuming a Poisson distribution for the number of events. Poisson regression modeling was used to examine the interactions with respect to prostate cancer mortality between trial arm and age, comorbidity status, and pretrial PSA testing. All statistical tests were two-sided. RESULTS Approximately 92% of the study participants were followed to 10 years and 57% to 13 years. At 13 years, 4250 participants had been diagnosed with prostate cancer in the intervention arm compared with 3815 in the control arm. Cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10 000 person-years, respectively, resulting in a relative increase of 12% in the intervention arm (RR = 1.12, 95% CI = 1.07 to 1.17). After 13 years of follow-up, the cumulative mortality rates from prostate cancer in the intervention and control arms were 3.7 and 3.4 deaths per 10 000 person-years, respectively, resulting in a non-statistically significant difference between the two arms (RR = 1.09, 95% CI = 0.87 to 1.36). No statistically significant interactions with respect to prostate cancer mortality were observed between trial arm and age (P(interaction) = .81), pretrial PSA testing (P(interaction) = .52), and comorbidity (P(interaction) = .68). CONCLUSIONS After 13 years of follow-up, there was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing.

The Risk of Stomach Cancer in Patients with Gastric or Duodenal Ulcer Disease

BACKGROUND Helicobacter pylori infection, now considered to be a cause of gastric cancer, is also strongly associated with gastric and duodenal ulcer disease. The discovery of these relations has brought the long-controversial connection between peptic ulcers and gastric cancer into focus. METHODS We estimated the risk of stomach cancer in a large cohort of hospitalized patients with gastric or duodenal ulcers, as recorded in the Swedish Inpatient Register between 1965 and 1983. Altogether, 57,936 patients were followed through 1989, for an average of 9.1 years. The standardized incidence ratio--the ratio of the observed number of cancers to the number expected on the basis of the incidence in the Swedish population at large--was used as a measure of relative risk. RESULTS After peaking in the first 3 years of follow-up, the standardized incidence ratio for gastric cancer among 29,287 patients with gastric ulcers leveled off at 1.8 (95 percent confidence interval, 1.6 to 2.0) and remained significantly increased throughout follow-up, which was as long as 24 years for some patients. Prepyloric ulcer, diagnosed in 8646 patients, was not associated with a significant excess risk (standardized incidence ratio, 1.2; 95 percent confidence interval, 0.8 to 1.6). In the cohort of patients with duodenal ulcers (24,456 patients), the incidence of gastric cancer was significantly lower than expected. After the second year of follow-up, the standardized incidence ratio was only 0.6 (95 percent confidence interval, 0.4 to 0.7) and remained stable thereafter. CONCLUSIONS Gastric ulcer disease and gastric cancer have etiologic factors in common. A likely cause of both is atrophic gastritis induced by H. pylori. By contrast, there appear to be factors associated with duodenal ulcer disease that protect against gastric cancer.

Genome-wide association study of circulating vitamin D levels

Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10−17) and rs10882272 (P =6.04× 10−12). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses’ Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10−5), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10−5). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases.

Prostate cancer epidemiology.

Prostate cancer is the most common non-skin cancer among men in most western populations, and it is the second leading cause of cancer death among U.S. men. Despite its high morbidity, the etiology of prostate cancer remains largely unknown. Advancing age, race, and a family history of prostate cancer are the only established risk factors. Many putative risk factors, including androgens, diet, physical activity, sexual factors, inflammation, and obesity, have been implicated, but their roles in prostate cancer etiology remain unclear. It is estimated that as much as 42% of the risk of prostate cancer may be accounted for by genetic influences, including individual and combined effects of rare, highly penetrant genes, more common weakly penetrant genes, and genes acting in concert with each other. Numerous genetic variants in the androgen biosynthesis/metabolism, carcinogen metabolism, DNA repair, and chronic inflammation pathways, have been explored, but the results are largely inconclusive. The pathogenesis of prostate cancer likely involves interplay between environmental and genetic factors. To unravel these complex relationships, large well-designed interdisciplinary epidemiologic studies are needed. With newly available molecular tools, a new generation of large-scale multidisciplinary population-based studies is beginning to investigate gene-gene and gene-environment interactions. Results of these studies may lead to better detection, treatment, and, ultimately, prevention of prostate cancer.

International trends and patterns of primary liver cancer

Primary liver cancer (PLC) is common in many areas of the developing world, but uncommon in most of the developed world. Some evidence suggests, however, that the global pattern of PLC may be changing. To clarify this issue, we examined incidence rates for PLC over the 15‐year time period, 1978–92, in selected cancer registries around the world. With some exceptions, developed countries have experienced PLC increases in incidence whereas developing countries have experienced declines. Although the reasons for the trends are not entirely clear, the increased seroprevalence of HCV in the developed world and the elimination of HBV‐cofactors in the developing world are likely to have contributed to the patterns. Further progress against PLC may be seen in the developing world once the HBV‐vaccinated segment of the population reaches adulthood. Published 2001 Wiley‐Liss, Inc.

Obesity, diabetes, and risk of prostate cancer: Results from the prostate cancer prevention trial

Studies on the relationship between obesity and prostate cancer incidence are inconsistent. In part, this inconsistency may be due to a differential effect of obesity on low-grade and high-grade cancer or confounding of the association of obesity with prostate cancer risk by diabetes. We investigated the associations of obesity and diabetes with low-grade and high-grade prostate cancer risk. Data were from 10,258 participants (1,936 prostate cancers) in the Prostate Cancer Prevention Trial who all had cancer presence or absence determined by prostate biopsy. Multiple logistic regression was used to model the risk of total prostate cancer, and polytomous logistic regression was used to model the risk of low-grade and high-grade prostate cancer. Compared with men with body mass index < 25, obese men (body mass index ≥30) had an 18% [odds ratio (OR), 0.82; 95% confidence interval (95% CI), 0.69-0.98] decreased risk of low-grade prostate cancer (Gleason <7) and a 29% (OR, 1.29; 95% CI, 1.01-1.67) increased risk of high-grade prostate cancer (Gleason ≥7) or, alternatively, a 78% (OR, 1.78; 95% CI, 1.10-2.87) increased risk defining high-grade cancer as Gleason sum 8 to 10. Diabetes was associated with a 47% (OR, 0.53; 95% CI, 0.34-0.83) reduced risk of low-grade prostate cancer and a 28% (OR, 0.72; 95% CI, 0.55-0.94) reduced risk of high-grade prostate cancer. Associations of obesity or diabetes with cancer risk were not substantially changed by mutually statistical controlling for each other. Obesity increases the risk of high-grade but decreases the risk of low-grade prostate cancer, and this relationship is independent of the lower risk for prostate cancer among men with diabetes. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1977–83)

Obesity, metabolic syndrome, and prostate cancer.

Although obesity has been consistently linked to an increased risk of several malignancies, including cancers of the colon, gallbladder, kidney, and pancreas, its role in prostate cancer etiology remains elusive. Data on the association between obesity and prostate cancer incidence are inconsistent, and in some studies obesity is associated with an increase in risk of high-grade prostate cancer but with a decrease in risk of low-grade tumors. In contrast, obesity has been consistently associated with an increased risk of prostate cancer aggressiveness and mortality. The differential effects of obesity on subtypes of prostate cancer suggest etiologic heterogeneity in these tumors and complex interactions between androgen metabolism and several putative risk factors, including insulin resistance, diabetes, inflammation, and genetic susceptibility, on prostate cancer risk. Data on the role of abdominal obesity, insulin resistance, and metabolic syndrome in prostate cancer etiology are limited. Obesity has been shown to be associated with a state of low-grade chronic inflammation, and insulin resistance and the metabolic syndrome are associated with adverse metabolic profiles and with higher circulating concentrations of inflammation-related markers, including leptin, interleukin-6, and tumor necrosis factor-, many of which have been shown to enhance tumor growth. Thus, whether obesity and metabolic syndrome modulate the risk of prostate cancer through chronic inflammation needs to be investigated further. Given that the prevalence of obesity and metabolic syndrome is increasing worldwide and that the world population is aging, the roles of obesity and metabolic syndrome in prostate carcinogenesis warrant further clarification.

Insulin-like Growth Factors, Their Binding Proteins, and Prostate Cancer Risk: Analysis of Individual Patient Data from 12 Prospective Studies

Context Insulin-like growth factors (IGFs) and IGF binding proteins may be associated with some cancers. Contribution This reanalysis of individual patient data from 12 studies of the association between IGFs and IGF binding proteins and prostate cancer suggests that higher levels of serum IGF-I are associated with higher risk for prostate cancer. Caution The 12 studies varied in the types of patients they studied and in how they measured IGFs. Implication High IGF-I levels seem to be a risk factor for prostate cancer. The Editors Prostate cancer is one of the most common types of cancer in men, yet few risk factors for the disease, other than age, race, and a family history, have been established (1, 2). Insulin-like growth factors (IGFs) and their associated binding proteins (IGFBPs) have been the subject of many epidemiologic investigations of prostate cancer because they are known to help regulate cell proliferation, differentiation, and apoptosis (3). Although results from some, but not all, studies suggest an association between IGFs and IGFBPs and prostate cancer risk, there has been much uncertainty about its consistency and magnitude. A previous meta-analysis that included only 3 prospective studies suggested that high levels could be associated with more than a 2-fold increase in risk (4), although recent studies have suggested the risk is lower. Furthermore, given that these peptides are correlated with each other, uncertainty remains about any observed relationships. The individual studies are rarely large enough to allow proper mutual adjustment for these correlated factors, and they are insufficiently powered to investigate the consistency of their findings in key subgroups (for example, stage and grade of disease). Such analyses are important because studies have suggested that IGF-I might be more associated with advanced than with localized disease (5, 6). The Endogenous Hormones and Prostate Cancer Collaborative Group was established to conduct collaborative reanalyses of individual data from prospective studies on the relationships between circulating levels of sex hormones and IGFs and subsequent prostate cancer risk. Results for the sex hormones have been reported elsewhere and show no statistically significant relation between androgen or estrogen levels in men and the subsequent risk for prostate cancer (7). We report results for concentrations of IGFs and IGFBPs. Methods Participants The Endogenous Hormones and Prostate Cancer Collaborative Group is described in detail elsewhere (7). In brief, the group invited principal investigators of all studies, found by searching PubMed, Web of Science, and CancerLit, that provided data on circulating concentrations of sex steroids, IGFs or IGFBPs, and prostate cancer risk by using prospectively collected blood samples to join the collaboration. Thirteen studies collected data on circulating IGF concentrations and the subsequent risk for prostate cancer (5, 6, 820), of which 1 contributed only data on sex hormones (20). Eleven of the studies used a matched casecontrol design nested within a prospective cohort study (5, 6, 812, 16, 19) or a randomized trial (1315, 17). One study used a casecohort design (18) and was converted into a matched casecontrol design by randomly matching up to 3 control participants to each case patient by age at recruitment, time between blood collection and diagnosis, time of blood draw, and race. (Table 1 provides a full description of the studies and matching criteria used.) Most of the prospective studies were population-based, with the exception of 1 based on health plan members (9), 1 that recruited male health professionals (16), and 1 that was a combination of an intervention study and a monitoring study for cardiovascular disease (6, 10). Two of the randomized trials did not have prostate cancer as a primary end point (5, 8, 15); the other 2 were based within a screening trial (13) or were about treatment of prostate-specific antigen (PSA)detected prostate cancer (14). Table 1. Study Characteristics Individual participant data were available for age; height; weight; smoking status; alcohol consumption; marital status; socioeconomic status (assessed by educational achievement); race; concentrations of IGFs, IGFBPs, and endogenous sex steroids; and PSA level. Information sought about prostate cancer included date of diagnosis, stage and grade of disease, and method of case patient ascertainment. Some studies (5, 6, 8, 10, 16) published more than 1 article or performed assays at different times on the association between IGFs and prostate cancer risk, sometimes with different matched casecontrol sets, laboratory measurements, and durations of follow-up. For each study, we created a single data set in which each participant appeared only once. In our analysis, we treated any participant who appeared in a study as both a control participant and a case patient as a case patient only. We removed matched set identifiers, and we generated a series of strata (equivalent to matched sets) in which participants in each study were grouped according to age at recruitment (2-year age bands) and date of recruitment (by year), because these matching criteria were common to most studies (Table 1). The number of strata used in the collaborative analysis was slightly less than that of matched sets used in the original analyses. To ensure that this process did not introduce any bias, we checked that the results for each study, using the original matched sets, were the same as those using the strata described above. Tumors were classified as advanced if the tumor was described as extending beyond the prostate capsule (T3/T4), and/or there was lymph node involvement (N1/N2/N3), and/or there were distant metastases (M1); tumors were classified as localized if they were T0/T1/T2 and N0/NX and M0. We classified tumors as high-grade if they had a Gleason score of 7 or more or were moderately poorly or poorly differentiated; otherwise, they were classified as low-grade. Statistical Analysis We calculated partial correlation coefficients between log-transformed IGF and IGFBP concentrations among control participants, adjusted for age at blood collection (<50, 50 to 59, 60 to 69, or 70 years) and study. For each IGF and IGFBP, we categorized men into quintiles of IGF and IGFBP serum concentrations, with cut-points defined by the study-specific quintiles of the distribution within control participants. For studies with more than 1 publication or in which the serum assays were done at different times, resulting in different absolute levels of IGFs (5, 6, 8, 10, 16), we calculated cut-points separately for each substudy. We used a conditional logistic regression stratified by study, age at recruitment (2-year age bands), and date of recruitment (single year) as our main method of analysis. To provide a summary measure of risk, we calculated a linear trend by scoring the quintiles of the serum IGF or IGFBP concentrations as 0, 0.25, 0.5, 0.75, and 1. Under the assumption of linearity, a unit change in this trend variable is equivalent to the odds ratio (OR) comparing the highest with the lowest quintile. All results are unadjusted for participant characteristics, except for those controlled by the stratification variables. We examined the possible influence of 5 participant characteristics by adjusting the relevant conditional logistic regression models for body mass index (BMI) (<22.5, 22.5 to 24.9, 25.0 to 27.4, 27.5 to 29.9, or >30 kg/m2), marital status (married or cohabiting, or not married or cohabiting), educational status (did not attend college or university, or attended college or university), smoking (never, previous, or current), and alcohol consumption (<10 or 10 g/d). We excluded participants from the analysis if they had a missing value for the characteristic under examination. We assessed heterogeneity in linear trends among studies by using a chi-square statistic to test whether the study-specific ORs were statistically different from the overall OR (21). Heterogeneity among studies was also quantified by calculating the H and I 2 statistics (22). To test whether the linear trend OR estimates for each IGF and IGFBP varied according to case patient characteristics, we estimated a series of subsets for each characteristic: stage at diagnosis (localized or advanced), grade at diagnosis (low or high), year of diagnosis (before 1990, 1990 to 1994, or 1995 onward; these year cutoffs were chosen to attempt to reflect differences in the use of the PSA test for cancer detection), age at diagnosis (<60, 60 to 69, or 70 years), and time between blood collection and diagnosis (<3, 3 to 6, or 7 years). We excluded case patients from the analyses of stage and grade at diagnosis if the relevant information was not available. For each of these case patient characteristics, we calculated a heterogeneity chi-square statistic to assess whether the estimated ORs statistically differed from each other (21). To assess whether the OR estimate of the linear trend for each IGF or IGFBP varied according to PSA level at recruitment (<2 g/L or 2 g/L), we entered an interaction term into the conditional logistic regression model for each IGF or IGFBP, and we tested the statistical significance of the interaction term with a likelihood ratio test. Statistical significance was set at the 5% level. All statistical tests were 2-sided. All statistical analyses were done with Stata, version 9.0 (StataCorp, College Station, Texas). Results Table 1 shows the characteristics of the studies. The 12 prospective studies included approximately 3700 case patients with prostate cancer and 5200 control participants. Insulin-like growth factor I and IGFBP-III measurements were available for all and 3600 case patients, respectively. However, IGF-II and IGFBP-II measurements were available for only 379 and 419 case patients, respectively (Table 2). Mean age at blood collection

Risk factors for colorectal cancer in a prospective study among U.S. white men

The association of diet, smoking/drinking and occupation with subsequent risk of fatal colorectal cancer was investigated in a cohort of 17,633 white males aged 35 and older, who completed a mail questionnaire in 1966. During the subsequent 20 years of follow‐up, 120 colon cancer and 25 rectal cancer deaths were identified. Due to small numbers, no significant dose‐response trends were observed in the study, but risk of colon cancer was elevated among heavy cigarette smokers (≥30/day; RR = 2.3, 95% CI 0.9–5.7), heavy beer drinkers (≥14 times/month; RR = 1.9, 95% CI 1.0–3.8) and white‐collar workers (RR = 1.7, 95% CI 1.0–3.0) or crafts workers within service and trade industries (RR = 2.6, 95% CI 1.1–5.8). In addition, an increased risk was seen for those who consumed red meat more than twice a day (RR = 1.8, 95% CI 0.8–4.4). Risk patterns for cancers of the colon and rectum combined were similar to those reported for cancer of the colon, but the estimates were somewhat dampened. Our findings support previous reports that a high intake of red meat and a sedentary life‐style may increase the risk of colon cancer. Int. J. Cancer77:549–553, 1998. Published 1998 Wiley‐Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.