Tom Grotmol

Risk of colorectal cancer seven years after flexible sigmoidoscopy screening: randomised controlled trial

Objective To determine the risk of colorectal cancer after screening with flexible sigmoidoscopy. Design Randomised controlled trial. Setting Population based screening in two areas in Norway—city of Oslo and Telemark county (urban and mixed urban and rural populations). Participants 55 736 men and women aged 55-64 years. Intervention Once only flexible sigmoidoscopy screening with or without a single round of faecal occult blood testing (n=13 823) compared with no screening (n=41 913). Main outcome measures Planned end points were cumulative incidence and mortality of colorectal cancer after 5, 10, and 15 years. This first report from the study presents cumulative incidence after 7 years of follow-up and hazard ratio for mortality after 6 years. Results No difference was found in the 7 year cumulative incidence of colorectal cancer between the screening and control groups (134.5 v 131.9 cases per 100 000 person years). In intention to screen analysis, a trend towards reduced colorectal cancer mortality was found (hazard ratio 0.73, 95% confidence interval 0.47 to 1.13, P=0.16). For attenders compared with controls, a statistically significant reduction in mortality was apparent for both total colorectal cancer (hazard ratio 0.41, 0.21 to 0.82, P=0.011) and rectosigmoidal cancer (0.24, 0.08 to 0.76, P=0.016). Conclusions A reduction in incidence of colorectal cancer with flexible sigmoidoscopy screening could not be shown after 7 years’ follow-up. Mortality from colorectal cancer was not significantly reduced in the screening group but seemed to be lower for attenders, with a reduction of 59% for any location of colorectal cancer and 76% for rectosigmoidal cancer in per protocol analysis, an analysis prone to selection bias. Trial registration Clinical trials NCT00119912.

The Norwegian Colorectal Cancer Prevention (NORCCAP) screening study: baseline findings and implementations for clinical work-up in age groups 50-64 years.

Background: Randomized controlled trials of sufficient power testing the long-term effect of screening for colorectal neoplasia only exist for faecal occult blood testing (FOBT). There is indirect evidence that flexible sigmoidoscopy (FS) may have a greater yield. The aim of this study was to determine the diagnostic yield of screening with FS or a combination of FS and FOBT in an average-risk population in an urban and combined urban and rural population in Norway. Methods: 20,780 men and women (1:1), aged 50-64 years, were invited for once-only screening (FS only or a combination of FS and FOBT (1:1)) by randomization from the population registry. A positive FS was defined as a finding of any neoplasia or any polyp S 10 r mm. A positive FS or FOBT qualified for colonoscopy. Results: Overall attendance was 65%. Forty-one (0.3%) cases of CRC were detected. Any adenoma was found in 2208 (17%) participants and 545 (4.2%) had high-risk adenomas. There was no difference in diagnostic yield between the FS and the FS and FOBT group regarding CRC or high-risk adenoma. Work-up load comprised 2821 colonoscopies in 2524 (20%) screenees and 10% of screenees were recommended later colonoscopy surveillance. There were no severe complications at FS, but six perforations after therapeutic colonoscopy (1:336). Conclusions: The present study bodes well for future management of a national screening programme, provided that follow-up results reflect adequate proof of a net benefit. It is highly questionable whether the addition of once-only FOBT to FS will contribute to this effect.BACKGROUND Randomized controlled trials of sufficient power testing the long-term effect of screening for colorectal neoplasia only exist for faecal occult blood testing (FOBT). There is indirect evidence that flexible sigmoidoscopy (FS) may have a greater yield. The aim of this study was to determine the diagnostic yield of screening with FS or a combination of FS and FOBT in an average-risk population in an urban and combined urban and rural population in Norway. METHODS 20,780 men and women (1:1), aged 50-64 years, were invited for once-only screening (FS only or a combination of FS and FOBT (1:1)) by randomization from the population registry. A positive FS was defined as a finding of any neoplasia or any polyp > or = 10 mm. A positive FS or FOBT qualified for colonoscopy. RESULTS Overall attendance was 65%. Forty-one (0.3%) cases of CRC were detected. Any adenoma was found in 2208 (17%) participants and 545 (4.2%) had high-risk adenomas. There was no difference in diagnostic yield between the FS and the FS and FOBT group regarding CRC or high-risk adenoma. Work-up load comprised 2821 colonoscopies in 2524 (20%) screenees and 10% of screenees were recommended later colonoscopy surveillance. There were no severe complications at FS, but six perforations after therapeutic colonoscopy (1:336). CONCLUSIONS The present study bodes well for future management of a national screening programme, provided that follow-up results reflect adequate proof of a net benefit. It is highly questionable whether the addition of once-only FOBT to FS will contribute to this effect.

NORCCAP (Norwegian colorectal cancer prevention): a randomised trial to assess the safety and efficacy of carbon dioxide versus air insufflation in colonoscopy

Background: To eliminate the risk of combustion during electrosurgical procedures and to reduce patient discomfort, carbon dioxide (CO2) insufflation has been recommended during colonoscopy. However, air insufflation is still the standard method, perhaps due to the lack of suitable equipment and shortage of randomised studies. Aims: This randomised controlled trial was conducted to assess patient tolerance and safety when using CO2 insufflation during colonoscopy. Patients: Over an eight month period a successive series of patients referred for a baseline colonoscopy due to findings in a flexible sigmoidoscopy screening trial were randomly assigned to the use of either air or CO2 insufflation during colonoscopy. Methods: End tidal CO2 (ETCO2), a non-invasive parameter of arterial pCO2, was registered before and repeatedly during and after the examination. The patients experience of pain during and after the examination was registered using a visual analogue scale (VAS). Sedation was not used routinely. Results: CO2 insufflation was used in 121 patients (51%) and air in 119 patients (49%). The groups were similar in age, sex, and caecal intubation rate. No rise in ETCO2 was registered. There were statistically significant differences in VAS scores between the groups with less pain reported when using CO2. Conclusions: This randomised study of unsedated patients shows that CO2 insufflation is safe during colonoscopy with no rise in ETCO2 level. CO2 was found to be superior to air in terms of pain experienced after the examination.

The Methylenetetrahydrofolate Reductase 677C→T Polymorphism as a Modulator of a B Vitamin Network with Major Effects on Homocysteine Metabolism

Folates are carriers of one-carbon units and are metabolized by 5,10-methylenetetrahydrofolate reductase (MTHFR) and other enzymes that use riboflavin, cobalamin, or vitamin B6 as cofactors. These B vitamins are essential for the remethylation and transsulfuration of homocysteine, which is an important intermediate in one-carbon metabolism. We studied the MTHFR 677C-->T polymorphism and B vitamins as modulators of one-carbon metabolism in 10,601 adults from the Norwegian Colorectal Cancer Prevention (NORCCAP) cohort, using plasma total homocysteine (tHcy) as the main outcome measure. Mean concentrations of plasma tHcy were 10.4 micromol/liter, 10.9 micromol/liter, and 13.3 micromol/liter in subjects with the CC (51%), CT (41%), and TT (8%) genotypes, respectively. The MTHFR 677C-->T polymorphism, folate, riboflavin, cobalamin, and vitamin B6 were independent predictors of tHcy in multivariate models (P<.001), and genotype effects were strongest when B vitamins were low (P<or=.006). Conversely, the MTHFR polymorphism influenced B vitamin effects, which were strongest in the TT group, in which the estimated tHcy difference between subjects with vitamin concentrations in the lowest compared with the highest quartile was 5.4 micromol/liter for folate, 4.1 micromol/liter for riboflavin, 3.2 micromol/liter for cobalamin, and 2.1 micromol/liter for vitamin B6. Furthermore, interactions between B vitamins were observed, and B vitamins were more strongly related to plasma tHcy when concentrations of other B vitamins were low. The study provides comprehensive data on the MTHFR-B vitamin network, which has major effects on the transfer of one-carbon units. Individuals with the TT genotype were particularly sensitive to the status of several B vitamins and might be candidates for personalized nutritional recommendations.

Design, organization and management of a controlled population screening study for detection of colorectal neoplasia: Attendance rates in the NORCCAP study (Norwegian Colorectal Cancer Prevention)

Background: In the past three decades, the incidence of colorectal cancer (CRC) in Norway has doubled, surpassing all other Nordic countries for both men and women to become the most frequently diagnosed cancer. A small-scale, randomized study on flexible sigmoidoscopy (FS) screening in Telemark, Norway, has shown a reduction in accumulated CRC incidence after 13 years. The aim of our study was to evaluate the effect on CRC mortality and morbidity by screen detection of CRC and removal of precursor lesions (polypectomy), and to test out the management and organization mimicking a countrywide screening service. A total of 13,823 men and women (1:1), age 55-64 years, were drawn randomly from the population registries in Oslo (urban) and the county of Telemark (mixed urban and rural) and invited to have a screening examination. The rest of the relevant age cohorts constituted the control groups. In the screening group, 535 individuals were excluded according to exclusion criteria, rendering 13,288 individuals eligible for screening examination. Methods: A once only screening model was used. In the screening group, individuals were randomized to have a once only FS or a combination of FS and faecal occult blood test (FOBT). Results: The overall attendance rate was 8,849 out of 13,288 (67%); 73% in Telemark and 60% in Oslo. Attendance for FS only was 68% and 65% for combined FS&FOBT. Conclusions: The present FS/FS&FOBT screening study obtained a high acceptance rate for both screening modalities. The attendance rate was stable throughout the trial, suggesting an acceptable model for management of future countrywide screening.

Age-Incidence Curves of Nasopharyngeal Carcinoma Worldwide: Bimodality in Low-Risk Populations and Aetiologic Implications

The distinct geographic variation in the global incidence of nasopharyngeal carcinoma reflects a complex etiology involving viral, environmental, and genetic components. The high to intermediate rates observed in endemic areas contrast markedly with the uniformly low rates seen in much of the world. An interesting epidemiologic observation is the early peak in age-incidence curves observed in certain geographically disparate populations, suggestive of distinct causal entities and the possible exhaustion of susceptible individuals from the population at a certain age. The aim of this study was to systematically evaluate the age-incidence profiles of NPC worldwide on partitioning populations according to level of risk, in an effort to provide clues about the importance of early-in-life factors and genetic susceptibility. Using data from 23 high-quality population-based cancer registries for the period 1983-1997, a key finding was the consistent pattern of bimodality that emerged across low-risk populations, irrespective of geographic location. Continual increases in NPC risk by age up to a first peak in late adolescence/early adulthood (ages 15-24 years) were observed, followed by a second peak later in life (ages 65-79 years). No such early peak in NPC incidence by age group was evident among the high-risk populations studied. These findings are discussed according to existing lines of biological and epidemiologic evidence related to level of population risk, age at diagnosis, and histologic subtype. A modified model for NPC tumor development is proposed on the basis of these observations. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2356–65)

Lifestyle as a predictor for colonic neoplasia in asymptomatic individuals

BackgroundLifestyle is a well-established risk factor for colorectal cancer (CRC) and is also found to be associated with occurrence of adenomas. In the present study we evaluated risk factors for both low-risk adenomas and advanced neoplasia in asymptomatic individuals using a single-paged questionnaire. Aiming to see if the questionnaire was a useful tool in picking up high-risk individuals.MethodsA cross-sectional study was carried out within a randomised controlled colorectal cancer screening trial (n = 6961). The population comprised men and women born between 1946 and 1950. Before screening in year 2001 they were asked to fill in a questionnaire about their present lifestyle. Cases were categorised according to the most severe findings at screening. Analyses were then conducted to find risk factors associated with the presence of either low-risk adenomas or advanced neoplasia.ResultsThe response rate among attendees was 97% (3998/4111). Among these, 3447 (86%) had no neoplasia, 443 (11%) had low-risk adenomas, and 108 (3%) had advanced neoplasia. Low-risk adenomas were significantly associated with current smoking, and obesity. Participants with advanced neoplasia had a two-fold increased risk of not adhering to any of the selected lifestyle recommendations compared to controls. However, current smoking was the only variable that reached statistical significance in the multivariate analysis for these lesions. A dose-response relationship to the consumption of cigarettes per day was shown, where OR was 2.04 (CI 1.07–3.89) for the lowest consumption category.ConclusionThe present findings indicate that a short questionnaire may be adequate in picking up the most consistent associations between lifestyle risk factors and colorectal neoplasia. Smoking and BMI were found to be the most significant risk factors for neoplasia, but adhering to recommendations on diet, and physical activity seems also to be of importance.

Trends in colorectal cancer incidence in Norway by gender and anatomic site: an age-period-cohort analysis.

The purpose of this study was to examine the secular trend of colorectal cancer in Norway by gender and subsite. All new cases of cancer in proximal colon, distal colon and rectum diagnosed between 1958 and 1997 in Norway were included in the study, altogether 34 202 and 34 097 cases for men and women, respectively. The incidence data were fitted separately for each gender and subsite to an age–period–cohort model. An increase in incidence of colorectal cancer was seen from 1958 to 1997 for both men and women, although a moderate attenuation of the increase has taken place in the last 15–20 years. This observation is most pronounced for cancer of the distal colon, but is also evident for proximal colonic and rectal cancers. For the distal colon and rectum, the period effect is more important than the cohort effect for both genders, whilst opposite for the proximal colon. The main estimated trend for cohort effects is a steady increase for both men and women, apart from an unexpected drop in incidence among the cohorts born during or shortly after World War II. These findings indicate that different aetiological risk factors may act on cancers of the proximal and distal part of the large bowel and further suggest that exogenous risk factors acting very early in life may play a more important role for colorectal cancer than previously recognized.

Maternal health and pre- and perinatal characteristics in the etiology of testicular cancer: A prospective population- and register-based study on Norwegian males born between 1967 and 1995

Objectives: The aim of the present prospective study was to identify possible risk factors of testicular cancer (TC) in relation to gestation and birth.Methods: Based on data from compulsory birth and cancer registration in Norway, odds ratios (ORs) of TC were estimated.Results: Among 868068 males born between 1967 and 1995, 268 cases of germ cancer had developed by June 1996, 32 TCs before 5 years of age and 236 TCs thereafter, 48 cases being seminomas and 220 non-seminomas. There was a tendency of an inverse association between parity and TC. A previous finding from Sweden linking neonatal jaundice to risk of non-seminomas was confirmed (adjusted OR=2.1, 95 percent confidence interval [CI]=1.3-6.9). Significant associations were also seen for seminomas and TC diagnosed after 5 years of age. Maternal disease diagnosed before pregnancy increased the risk of TC significantly, particularly in the age group 0-4 years: Adjusted OR=3.0, CI=1.4-6.3. Retained placenta was significantly associated with both seminomas and non-seminomas and with TC diagnosed after 5 years of age.Conclusions: The findings of this study support the existing hypothesis that pre- and perinatal risk factors are of significance for development of TC in children and in young adults, and for seminomas and non-seminomas. The hypothesis that estrogens are involved in TC development was, among other factors, supported by the association of parity to TC. Additionally, on the basis of findings in maternal diseases and complications to pregnancy, we suggest that immune reactions during foetal life may be of significance for development of TC.

Testing for faecal calprotectin (PhiCal) in the Norwegian Colorectal Cancer Prevention trial on flexible sigmoidoscopy screening: comparison with an immunochemical test for occult blood (FlexSure OBT)

Background: Screening for colorectal cancer (CRC) using guaiac based faecal occult blood tests (FOBT) has an estimated programme sensitivity of >60% but <30% for strictly asymptomatic CRC in a single screening round. In search for improved non-invasive tests for screening, we compared a test for faecal calprotectin (PhiCal) with a human haemoglobin immunochemical FOBT (FlexSure OBT). Methods: In the Norwegian Colorectal Cancer Prevention (NORCCAP) trial, screenees in one screening arm were offered screening with combined flexible sigmoidoscopy (FS) and FlexSure OBT. They were also requested to bring a fresh frozen sample of stool for the PhiCal test which was performed on samples from screenees with CRC (n = 16), high risk adenoma (n = 195), low risk adenoma (n = 592), and no adenoma (n = 1518) (2321 screenees in total). A positive PhiCal test was defined by a calprotectin level ⩾50 μg/g. Results: The PhiCal test was positive in 24–27% of screenees whether they had no adenoma, low risk adenoma, or high risk adenoma. Ten (63%) of 16 CRCs gave a positive PhiCal test. The total positivity rate in this population was 25% for the PhiCal test compared with 12% for FlexSure OBT, with a sensitivity for advanced neoplasia of 27% and 35%, respectively. Specificity for “any neoplasia” was 76% for the PhiCal test and 90% for FlexSure OBT. Conclusions: In colorectal screening, the performance of the PhiCal test on a single spot from one stool sample was poorer than a single screening round with FlexSure OBT and cannot be recommended for population screening purposes. The findings indicate a place for FlexSure OBT in FOBT screening.