Mark P. Purdue

Colorectal-Cancer Incidence and Mortality with Screening Flexible Sigmoidoscopy

BACKGROUND The benefits of endoscopic testing for colorectal-cancer screening are uncertain. We evaluated the effect of screening with flexible sigmoidoscopy on colorectal-cancer incidence and mortality. METHODS From 1993 through 2001, we randomly assigned 154,900 men and women 55 to 74 years of age either to screening with flexible sigmoidoscopy, with a repeat screening at 3 or 5 years, or to usual care. Cases of colorectal cancer and deaths from the disease were ascertained. RESULTS Of the 77,445 participants randomly assigned to screening (intervention group), 83.5% underwent baseline flexible sigmoidoscopy and 54.0% were screened at 3 or 5 years. The incidence of colorectal cancer after a median follow-up of 11.9 years was 11.9 cases per 10,000 person-years in the intervention group (1012 cases), as compared with 15.2 cases per 10,000 person-years in the usual-care group (1287 cases), which represents a 21% reduction (relative risk, 0.79; 95% confidence interval [CI], 0.72 to 0.85; P<0.001). Significant reductions were observed in the incidence of both distal colorectal cancer (479 cases in the intervention group vs. 669 cases in the usual-care group; relative risk, 0.71; 95% CI, 0.64 to 0.80; P<0.001) and proximal colorectal cancer (512 cases vs. 595 cases; relative risk, 0.86; 95% CI, 0.76 to 0.97; P=0.01). There were 2.9 deaths from colorectal cancer per 10,000 person-years in the intervention group (252 deaths), as compared with 3.9 per 10,000 person-years in the usual-care group (341 deaths), which represents a 26% reduction (relative risk, 0.74; 95% CI, 0.63 to 0.87; P<0.001). Mortality from distal colorectal cancer was reduced by 50% (87 deaths in the intervention group vs. 175 in the usual-care group; relative risk, 0.50; 95% CI, 0.38 to 0.64; P<0.001); mortality from proximal colorectal cancer was unaffected (143 and 147 deaths, respectively; relative risk, 0.97; 95% CI, 0.77 to 1.22; P=0.81). CONCLUSIONS Screening with flexible sigmoidoscopy was associated with a significant decrease in colorectal-cancer incidence (in both the distal and proximal colon) and mortality (distal colon only). (Funded by the National Cancer Institute; PLCO ClinicalTrials.gov number, NCT00002540.).

Interaction between tobacco and alcohol use and the risk of head and neck cancer: Pooled analysis in the international head and neck cancer Epidemiology consortium

Background: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. Methods: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter (ψ) and population attributable risks (PAR). Results: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk (ψ = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases <45 years, 73% for cases >60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). Conclusions: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases. (Cancer Epidemiol Biomarkers Prev 2009;18(2):541–50)

Genome-wide association study of circulating vitamin D levels

The primary circulating form of vitamin D, 25-hydroxy-vitamin D [25(OH)D], is associated with multiple medical outcomes, including rickets, osteoporosis, multiple sclerosis and cancer. In a genome-wide association study (GWAS) of 4501 persons of European ancestry drawn from five cohorts, we identified single-nucleotide polymorphisms (SNPs) in the gene encoding group-specific component (vitamin D binding) protein, GC, on chromosome 4q12-13 that were associated with 25(OH)D concentrations: rs2282679 (P = 2.0 × 10−30), in linkage disequilibrium (LD) with rs7041, a non-synonymous SNP (D432E; P = 4.1 × 10−22) and rs1155563 (P = 3.8 × 10−25). Suggestive signals for association with 25(OH)D were also observed for SNPs in or near three other genes involved in vitamin D synthesis or activation: rs3829251 on chromosome 11q13.4 in NADSYN1 [encoding nicotinamide adenine dinucleotide (NAD) synthetase; P = 8.8 × 10−7], which was in high LD with rs1790349, located in DHCR7, the gene encoding 7-dehydrocholesterol reductase that synthesizes cholesterol from 7-dehydrocholesterol; rs6599638 in the region harboring the open-reading frame 88 (C10orf88) on chromosome 10q26.13 in the vicinity of ACADSB (acyl-Coenzyme A dehydrogenase), involved in cholesterol and vitamin D synthesis (P = 3.3 × 10−7); and rs2060793 on chromosome 11p15.2 in CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1, encoding a key C-25 hydroxylase that converts vitamin D3 to an active vitamin D receptor ligand; P = 1.4 × 10−5). We genotyped SNPs in these four regions in 2221 additional samples and confirmed strong genome-wide significant associations with 25(OH)D through meta-analysis with the GWAS data for GC (P = 1.8 × 10−49), NADSYN1/DHCR7 (P = 3.4 × 10−9) and CYP2R1 (P = 2.9 × 10−17), but not C10orf88 (P = 2.4 × 10−5).

Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium

BACKGROUND Sexual contact may be the means by which head and neck cancer patients are exposed to human papillomavirus (HPV). METHODS We undertook a pooled analysis of four population-based and four hospital-based case-control studies from the International Head and Neck Cancer Epidemiology (INHANCE) consortium, with participants from Argentina, Australia, Brazil, Canada, Cuba, India, Italy, Spain, Poland, Puerto Rico, Russia and the USA. The study included 5642 head and neck cancer cases and 6069 controls. We calculated odds ratios (ORs) of associations between cancer and specific sexual behaviours, including practice of oral sex, number of lifetime sexual partners and oral sex partners, age at sexual debut, a history of same-sex contact and a history of oral-anal contact. Findings were stratified by sex and disease subsite. RESULTS Cancer of the oropharynx was associated with having a history of six or more lifetime sexual partners [OR = 1.25, 95% confidence interval (CI) 1.01, 1.54] and four or more lifetime oral sex partners (OR = 2.25, 95% CI 1.42, 3.58). Cancer of the tonsil was associated with four or more lifetime oral sex partners (OR = 3.36, 95 % CI 1.32, 8.53), and, among men, with ever having oral sex (OR = 1.59, 95% CI 1.09, 2.33) and with an earlier age at sexual debut (OR = 2.36, 95% CI 1.37, 5.05). Cancer of the base of the tongue was associated with ever having oral sex among women (OR = 4.32, 95% CI 1.06, 17.6), having two sexual partners in comparison with only one (OR = 2.02, 95% CI 1.19, 3.46) and, among men, with a history of same-sex sexual contact (OR = 8.89, 95% CI 2.14, 36.8). CONCLUSIONS Sexual behaviours are associated with cancer risk at the head and neck cancer subsites that have previously been associated with HPV infection.

Serum Vitamin D Concentration and Prostate Cancer Risk: A Nested Case - Control Study

BACKGROUND Epidemiological studies have yielded inconsistent associations between vitamin D status and prostate cancer risk, and few studies have evaluated whether the associations vary by disease aggressiveness. We investigated the association between vitamin D status, as determined by serum 25-hydroxyvitamin D [25(OH)D] level, and risk of prostate cancer in a case-control study nested within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. METHODS The study included 749 case patients with incident prostate cancer who were diagnosed 1-8 years after blood draw and 781 control subjects who were frequency matched by age at cohort entry, time since initial screening, and calendar year of cohort entry. All study participants were selected from the trial screening arm (which includes annual standardized prostate cancer screening). Conditional logistic regression was used to estimate adjusted odds ratios (ORs) with 95% confidence intervals (CIs) by quintile of season-standardized serum 25(OH)D concentration. Statistical tests were two-sided. RESULTS No statistically significant trend in overall prostate cancer risk was observed with increasing season-standardized serum 25(OH)D level. However, serum 25(OH)D concentrations greater than the lowest quintile (Q1) were associated with increased risk of aggressive (Gleason sum > or = 7 or clinical stage III or IV) disease (in a model adjusting for matching factors, study center, and history of diabetes, ORs for Q2 vs Q1 = 1.20, 95% CI = 0.80 to 1.81, for Q3 vs Q1 =1.96, 95% CI = 1.34 to 2.87, for Q4 vs Q1 = 1.61, 95% CI = 1.09 to 2.38, and for Q5 vs Q1 = 1.37, 95% CI = 0.92 to 2.05; P(trend) = .05). The rates of aggressive prostate cancer for increasing quintiles of serum 25(OH)D were 406, 479, 780, 633, and 544 per 100 000 person-years. In exploratory analyses, these associations with aggressive disease were consistent across subgroups defined by age, family history of prostate cancer, diabetes, body mass index, vigorous physical activity, calcium intake, study center, season of blood collection, and assay batch. CONCLUSION The findings of this large prospective study do not support the hypothesis that vitamin D is associated with decreased risk of prostate cancer; indeed, higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease.

Recent trends in incidence of cutaneous melanoma among US Caucasian young adults.

TO THE EDITOR: Recent findings suggest that non-melanoma skin cancer (NMSC) incidence in young adults is rising, particularly among U.S. young women (Christenson et al., 2005). This raises the important question of whether incidence of cutaneous melanoma, the most lethal form of skin cancer, is similarly increasing in young adults. While melanoma incidence among U.S. older adults has been increasing for several decades, there have been indications that incidence may be stabilizing for birth cohorts born after 1945 (Dennis et al., 1993;Hall et al., 1999). However, in an analysis of melanoma trends between 1973 and 1997 in the Surveillance, Epidemiology, and End Results (SEER) Program, Jemal et al. noted evidence of an increase among women born after 1960 (Jemal et al., 2001). Since that analysis, an additional seven years of SEER data have been collected. To better understand recent trends in melanoma incidence among young adults, we report findings from a re-analysis of SEER data, extended through 2004. Our analysis was restricted to Caucasians from the nine registries that have contributed data to the SEER Program since 1973 (Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle, Utah). We calculated annual age-adjusted incidence (SEER Progam, 2007a) and mortality rates (SEER Program, 2007b) of invasive cutaneous melanoma among men and women aged 15–39, standardized to the 2000 U.S. population, using the software SEER*Stat version 6.3.6 (National Cancer Institute: http://seer.cancer.gov/seerstat/). We assessed trends in greater detail using joinpoint regression models, which identify changes in trends over successive segments of time and describe the estimated annual percent change (EAPC) in incidence within each segment (Kim et al., 2000), using the software Joinpoint version 3.0 (National Cancer Institute: http://srab.cancer.gov/joinpoint/). Joinpoint analyses stratifying by melanoma stage (localized vs. regional/distant) and thickness (≤1mm vs. >1mm) were also performed. To describe age-specific trends by year of birth, we calculated incidence by five-year age groups and time periods, and plotted age-specific incidence by calendar year of birth (calculated from the age group midpoint). Additionally, age-period-cohort modeling was used to simultaneously adjust age-specific incidence trends for both calendar period and birth cohort effects (Tarone and Chu, 2000). All p-values are two-sided. Overall, the age-adjusted annual incidence of melanoma among young men increased from 4.7 cases per 100,000 persons (95% confidence limits 3.8, 5.7) in 1973 to 7.7 per 100,000 in 2004 (6.8, 8.7). Among women, age-adjusted annual incidence per 100,000 increased from 5.5 (4.5, 6.6) in 1973 to 13.9 (12.7, 15.2) in 2004. Melanoma incidence increased among young men (EAPC=6.6; 95% CL 2.9, 10.4) and women (9.2; 6.8, 11.7) during the 1970s (Figure 1, Table 1). Starting around 1980, this pattern changed. For men, incidence leveled off between 1980 and 2004 (0.4; −0.2, 0.9). For women, the rate of increase in incidence declined from 1978 to 1987 (2.6; 1.5, 3.8) and stabilized from 1987 to 1992 (−0.6; −3.7, 2.6). After 1992, however, incidence began climbing again (2.7; 2.1, 3.4). Incidence among women from the 1990s onward increased both for thinner and thicker melanomas (≤1mm: 3.1; 2.5, 3.6. >1mm: 2.8; 1.6, 4.0), and was greater for regional and distant tumors (9.2; 3.8, 14.9) compared to localized lesions (1.9; 1.6, 2.3). Melanoma mortality rates for men and women declined from 1981 onward (men: −3.6; −4.5, −2.7. women: −2.3; −3.1, −1.5). Figure 1 Age-adjusted (to 2000 U.S. population) annual cutaneous melanoma incidence and mortality rates among Caucasian males and females aged 15–39 in the Surveillance, Epidemiology, and End Results Program areas from 1973 through 2004. The segments of ... Table 1 Estimated annual percent changes (EAPC) in incidence of melanoma and melanoma mortality among Caucasian males and females aged 15–39 in the SEER Program from 1973 through 2004. Age-specific incidence patterns by year of birth are presented in Figure 2. Male age-specific incidence rose steadily with each successive birth cohort until 1950, at which time incidence appeared to level off or decrease slightly. Female age-specific incidence by birth cohort increased steadily until around 1950; thereafter, incidence appeared to climb at a slower pace until 1965, at which point incidence appeared to begin accelerating. After adjustment for age and period effects, age-period-cohort modeling confirmed a change in the effect of birth cohort for women born between 1960 and 1965 (Supplementary Figure; slope change parameter = 0.2146; 95% CL 0.0576, 0.3716; p=0.007). Figure 2 Age-specific melanoma incidence among Caucasians stratified by sex and birth-cohort year in the SEER program from 1975–1979 through 2000–2004. The points vertically above each cohort year portray the cohort’s age-specific incidence ... It is important to consider whether these trends may reflect changes in data quality, diagnosis or surveillance. There is evidence of increased underreporting of melanoma over time within the SEER program, with estimates as high as 17% of all cases (including in situ lesions) in two registries, although such a trend in underreporting cannot explain the observed increase in incidence among women (Seiffert, 1992;Merlino et al., 1997). It is unlikely that a change in melanoma diagnostic criteria would account for our finding, since the effect of such a change would not be expected to be sex-specific. Changes in screening patterns may have led to earlier detection within this time period, with a higher rate of increase seen among superficial localized tumors compared to thicker lesions and regional or metastatic disease overall (Jemal et al., 2001;Welch et al., 2005). Indeed, the observed decrease in melanoma mortality rates after 1981 and previously reported evidence of general improvement in survival by stage over this time period are consistent with a shift towards earlier detection of disease through increased surveillance (Jemal et al., 2001). However, in our analysis, the increasing trend among young women from the early 1990s onward was also observed for thicker and regional/distant tumors, which are less susceptible to misclassification. Moreover, our age-period-cohort analysis suggested that, after adjusting for age and period effects (the latter of which is reflective of changes in disease surveillance), the observed increase in incidence among women born after 1965 is consistent with a birth cohort effect (indicative of changes in disease risk factor prevalence across birth cohorts; (Tarone and Chu, 2000)). Thus, our findings are compatible with a real increase in incidence among young women, although we cannot rule out the effects of changes in surveillance. The recent increase in incidence among young women parallels reported trends in exposure to ultraviolet radiation (UVR), the primary environmental cause of melanoma (Armstrong and Kricker, 2001). The prevalence of sunburn is increasing among U.S. adult men and women overall, although trends by age group have not been reported (Robinson et al., 1997;Saraiya et al., 2007). Among adolescents aged 16–18, both the prevalence of sunburn and the average number of days spent at the beach increased between sun surveys conducted in 1998 and 2004 (Cokkinides et al., 2006). Tanning bed usage, which has been recently evaluated as a probable cause of melanoma (International Agency for Research on Cancer, 2007), is increasing among U.S. adults and is most prevalent among young women (Robinson et al., 1997;Lazovich and Forster, 2005). In conclusion, our analysis of SEER data suggests that melanoma incidence is increasing among young women. Additional studies are needed in order to clarify whether the increasing trends for melanoma and NMSC (Christenson et al., 2005) are the result of changes in UVR exposure in this population.

Circulating 25-Hydroxyvitamin D and Risk of Pancreatic Cancer Cohort Consortium Vitamin D Pooling Project of Rarer Cancers

Results from epidemiologic studies examining pancreatic cancer risk and vitamin D intake or 25-hydroxyvitamin D (25(OH)D) concentrations (the best indicator of vitamin D derived from diet and sun) have been inconsistent. Therefore, the authors conducted a pooled nested case-control study of participants from 8 cohorts within the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) (1974–2006) to evaluate whether prediagnostic circulating 25(OH)D concentrations were associated with the development of pancreatic cancer. In total, 952 incident pancreatic adenocarcinoma cases occurred among participants (median follow-up, 6.5 years). Controls (n = 1,333) were matched to each case by cohort, age, sex, race/ethnicity, date of blood draw, and follow-up time. Conditional logistic regression analysis was used to calculate smoking-, body mass index-, and diabetes-adjusted odds ratios and 95% confidence intervals for pancreatic cancer. Clinically relevant 25(OH)D cutpoints were compared with a referent category of 50–<75 nmol/L. No significant associations were observed for participants with lower 25(OH)D status. However, a high 25(OH)D concentration (≥100 nmol/L) was associated with a statistically significant 2-fold increase in pancreatic cancer risk overall (odds ratio = 2.12, 95% confidence interval: 1.23, 3.64). Given this result, recommendations to increase vitamin D concentrations in healthy persons for the prevention of cancer should be carefully considered.

International trends in the incidence of testicular cancer, 1973–2002

Background: Whereas testicular cancer incidence rates have been widely reported in populations of Northern European ancestry, rates in other populations have been less frequently examined. In a prior report, global testicular cancer incidence rates and trends for the years 1973 to 1997 were summarized. The current report extends these analyses with an additional 5 years of data from Cancer Incidence in Five Continents. Methods: Age-standardized incidence rates over successive 5-year time periods were obtained for populations in the Americas, Asia, Europe, and Oceania. Results: In general, testicular cancer incidence remained highest in Northern European populations (8.0-9.0 per 100,000) and lowest in Asian and African populations (<1 per 100,000). One notable exception to this pattern, however, was the very high rate reported by the Valdivia, Chile registry (8.8 per 100,000). In many populations, rates rose between 1973 and 2002, although the increases were strongest and most consistent among populations of European ancestry. In certain European populations, such as those of Denmark and of Geneva, Switzerland, some recent plateauing of rates was evident. There was little evidence of increase and possible evidence of a modest decline in rates among east Asian populations. Trends by histology (seminoma and nonseminoma) were generally similar to one another. Conclusions: Risk of testicular cancer remains relatively high in Northern European populations and low in Asian and African populations. Similar trends by histology suggest common risk factors. Effect: Reasons for increasing rates among Northern Europeans and stable or declining rates among East Asians are unexplained, supporting the need for future etiologic studies. Cancer Epidemiol Biomarkers Prev; 19(5); 1151–9. ©2010 AACR.

International patterns and trends in testis cancer incidence

Although the incidence of testis cancer has risen markedly in many Western populations over the past half‐century, it is not clear whether rates in other populations also have increased. To clarify this issue, we examined testis cancer incidence rates over the 25‐year time period of 1973–1997 for selected populations around the world. Age‐standardized incidence rates for 21 registries in the Americas, Asia, Europe and Oceania over successive 5‐year time periods were obtained from volumes 4–8 of Cancer Incidence in Five Continents. Testis cancer rates rose between 1973 and 1997 in most populations worldwide, although the increases were strongest and most consistent among populations of European ancestry. Rates appear to be leveling off in some populations. The increases in testis cancer remain unexplained, although changes in the prevalence of important risk factors for this disease may be responsible. Published 2005 Wiley‐Liss, Inc.

Low vitamin D status is associated with physical inactivity, obesity and low vitamin D intake in a large US sample of healthy middle-aged men and women

The aim of this study was to investigate modifiable predictors of vitamin D status in healthy individuals, aged 55-74, and living across the USA. Vitamin D status [serum 25-hydroxyvitamin D (25(OH)D)] was measured along with age and season at blood collection, demographics, anthropometry, physical activity (PA), diet, and other lifestyle factors in 1357 male and 1264 female controls selected from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort. Multivariate linear and logistic regression analyses were used to identify associations with vitamin D status. Three%, 29% and 79% of the population had serum 25(OH)D levels<25, <50 and <80 nmol/L, respectively. The major modifiable predictors of low vitamin D status were low vitamin D dietary and supplement intake, body mass index (BMI) >30 kg/m2, physical inactivity (PA) and low milk and calcium supplement intake. In men, 25(OH)D was determined more by milk intake on cereal and in women, by vitamin D and calcium supplement and menopausal hormone therapy (MHT) use. Thus targeting an increase in vigorous activity and vitamin D and calcium intake and decreasing obesity could be public health interventions independent of sun exposure to improve vitamin D status in middle-aged Americans.