Nottingham trial of faecal occult blood testing for colorectal cancer: a 20-year follow-up.

BACKGROUND: Three large randomised trials have shown that screening for colorectal cancer (CRC) using the faecal occult blood test (FOBt) can reduce the mortality from this disease. The largest of these trials, conducted in Nottingham since 1981, randomised 152,850 individuals between the ages of 45 and 74 years to an intervention arm receiving biennial Haemoccult (FOB) test kit or to a control arm. In 2006, the National Bowel Cancer Screening Programme was launched in England using the FOBt, with the expectation that it will reduce CRC mortality. AIMS: To compare the CRC mortality and incidence in the intervention arm with the control arm after long-term follow-up. METHODS: The 152,850 randomised individuals were followed up through local health records and central flagging (Office for National Statistics). RESULTS: At a median follow-up of 19.5 years there was a 13% reduction in CRC mortality (95% CI 3% to 22%) in the intervention arm despite an uptake at first invitation of approximately 57%. The CRC mortality reduction in those accepting the first screening test, adjusted for the rate of non-compliers, was 18%. There was no significant difference in mortality from causes other than CRC between the intervention and control arms. Despite removing 615 adenomas >10 mm in size from the intervention arm, there was no significant difference in CRC incidence between the two arms. CONCLUSIONS: Although the reduction in CRC mortality was sustained, further follow-up of the screened population has not shown a significant reduction in the CRC incidence. Moreover, despite the removal of many large adenomas there was no reduction in the incidence of invasive cancer which was independent of sex and site of the tumour.

Analysis of deaths occurring within the Nottingham trial of faecal occult blood screening for colorectal cancer.

OBJECTIVE: To report the causes of, and ages at, death of subjects in an English colorectal cancer screening trial. DESIGN AND SETTING: Analysis of 78 708 deaths occurring between 1981 and 2008, within the Nottingham randomised controlled trial of biennial faecal occult blood testing. MAIN OUTCOME MEASURES: Cause of death, age at death by sex and by cause. RESULTS: Significantly more subjects died from verified colorectal cancer in the trial's control group than in the intervention group (3.2% vs 2.9%). For no other major cause of death was the difference in proportion across the two groups statistically significant. Age at death was lower for cancer than for other principal causes, except for ischaemic heart disease among women. However, mean age at death was higher for colorectal cancer than for other cancers, except for prostate cancer among men. Increasing levels of material deprivation significantly lowered the expected ages at death, independently of cause. For both men and women, the mean age at death from all causes for screening participants was higher than that of controls and non-participants. Mean deprivation was lowest among participants. Of those participating in screening, and dying from colorectal cancer, subjects receiving negative test results lived significantly longer than those who received positive test results. However, if dying from other causes, they died at an earlier age. CONCLUSIONS: The age at death from colorectal cancer is higher than that of most other cancers. Those accepting a screening invitation live longer than non-participants. In part, this difference is explained by relative deprivation. Among screening participants, the receipt of a positive, as opposed to a negative, test result is associated with a later age at death.

Effect of faecal occult blood screening on mortality from colorectal cancer: results from a randomised controlled trial.

BACKGROUND: Three large randomised trials have shown that screening for colorectal cancer using faecal occult blood (FOB) tests can reduce the mortality from this disease. Two national pilot studies have recently been launched in the UK to investigate the feasibility of population screening for colorectal cancer in the National Health Service. The largest of the randomised trials was conducted in Nottingham and randomised 152 850 individuals between the ages of 45 and 74 years to receive biennial Haemoccult (FOB) test kit (intervention group) or to a control group. AIMS: We have compared the mortality in the intervention group compared with the control group. METHODS: The 152 850 randomised individuals were followed up through local health records and central flagging (Office for National Statistics) over a median follow up period of 11 years. RESULTS: At a median follow up of 11 years there was a 13% reduction in colorectal cancer mortality (95% confidence interval 3-22%) in the intervention group despite an uptake at first invitation of only approximately 50%. The mortality reduction for those accepting screening was 27%. The reduction in mortality was independent of sex and site of tumour. There was no significant difference in mortality from causes other than colorectal cancer between the intervention and control groups. CONCLUSIONS: Although the reduction in colorectal cancer mortality was sustained, further follow up of this population is required to determine whether a significant reduction in the incidence of colorectal cancer will be achieved.

Faecal occult blood screening for colorectal cancer at Nottingham: details of the verification process.

Cause specific mortality statistics derived from death certificates are highly dependent upon the accuracy of certification by the attending physician. In the Nottingham colorectal cancer screening trial, there were 12,624 deaths among the screening group and 12,515 among the control group during the period under consideration. There was no significant difference in all cause mortality rate (excluding deaths due to colorectal cancer) between the two study groups (rate ratio = 1.01, 95% confidence interval = 0.99 to 1.03). Disease specific mortality rates did not differ significantly between the two groups either. Overall, the agreement between verified and certified cause of death was 86%. Using the certified cause of death would have resulted in an underestimation bias of 6.27% for colorectal cancer deaths.

The risks of screening: data from the Nottingham randomised controlled trial of faecal occult blood screening for colorectal cancer.

AIMS: To determine the harm that ensues from faecal occult blood (FOB) screening for colorectal cancer. METHODS: 150 251 people were randomly allocated either to receive biennial Haemoccult FOB tests (n =75 253) or not to be contacted (n=74 998). Study group patients returning positive tests were offered colonic investigation; 1774 underwent complete investigation of the colon. RESULTS: There was no significant difference in the stage at presentation of interval versus control group cancers. Survival in the interval cancer group was significantly prolonged compared with the control group. Sensitivity for colonoscopy or flexible sigmoidoscopy and double contrast barium enema (DCBE) was 96.7%. There were no complications of DCBE but seven (0.5%) complications of colonoscopy, of which six required surgical intervention. There were no colonoscopy related deaths. No patients without colorectal cancer died within 30 days of colonic investigation. Five patients died within 30 days of surgery for screen detected colorectal neoplasia and a further two died without having surgery. Six patients died after 30 days but within two years of surgery for screen detected benign adenomas or stage A cancers; in all cases the cause of death was not related to colorectal cancer. CONCLUSIONS: There was investigation related morbidity but no mortality and little to support overdiagnosis bias. The group returning falsely negative tests had a better outcome compared with the whole control group. There is a negative side to any screening programme but mortality reduction in this and other trials suggests that a national programme of colorectal cancer screening should be given consideration.

Screening for colorectal cancer reduces emergency admissions.

AIMS: Colorectal cancer is common and accounts for over 15,000 deaths annually in England and Wales. Up to 30% of these patients require emergency surgery. Screening for colorectal cancer can reduce the mortality of colorectal cancer. This study addresses the impact of a population-based screening study on emergency admissions with colorectal cancer. METHOD: From 1981 a randomized trial of Faecal Occult Blood (FOB) screening has been undertaken in the Nottingham area, recruiting over 150,000 patients. The present study examined the records of patients enrolled in this study who presented as an emergency with colorectal cancer. RESULTS: Colorectal cancer was identified in 1962 cases, of which 468 (23.9%) presented as emergencies. The overall compliance was 60% (proportion of individuals completing at least one test). There were significantly fewer emergencies in the Screen-detected group compared with the Control group (P = < 0.0001). This group also had a significantly reduced 30-day mortality and a lower stoma rate than the Control group. Conversely the Non-responders had a significantly greater proportion of emergency admissions and a significantly increased stoma rate compared with the Control group. CONCLUSIONS: Screening for colorectal cancer using a faecal occult blood test can significantly reduce the number of emergency presentations with colorectal cancer. It is likely that the introduction of a national programme of screening for colorectal cancer would lead to increased compliance and that this would lead to a significant reduction in the emergency workload on the National Health Service from colorectal cancer.

Randomised controlled trial of faecal-occult-blood screening for colorectal cancer.

BACKGROUND: There is growing evidence that faecal-occult-blood (FOB) screening may reduce colorectal cancer (CRC) mortality, but this reduction in CRC mortality has not been shown in an unselected population-based randomised controlled trial. The aim of this study was to assess the effect of FOB screening on CRC mortality in such a setting. METHODS: Between February, 1981, and January, 1991, 152,850 people aged 45-74 years who lived in the Nottingham area of the UK were recruited to our study. Participants were randomly allocated FOB screening (76,466) or no screening (controls; 76,384). Controls were not told about the study and received no intervention. Screening-group participants were sent a Haemoccult FOB test kit with instructions from their family doctor. FOB tests were not rehydrated and dietary restrictions were imposed only for retesting borderline results. Individuals with negative FOB tests at the first screening, together with those who tested positive but in whom no neoplasia was found on colonoscopy, were invited to take part in further screening every 2 years. Screening was stopped in February, 1995, by which time screening-group participants had been offered FOB tests between three and six times. Screening-group participants who had a positive test were offered full colonoscopy. All participants were followed up until June, 1995. The primary outcome measure was CRC mortality. FINDINGS: Of the 152,850 individuals recruited to the study, 2599 could not be traced or had emigrated and were excluded from the analysis. Thus, there were 75,253 participants in the screening group and 74,998 controls. 44,838 (59.6%) screening-group participants completed at least one screening. 28,720 (38.2%) of these individuals completed all the FOB tests they were offered and 16,118 (21.4%) completed at least one screening but not all the tests they were offered. 30,415 (40.4%) did not complete any test. Of 893 cancers (20% stage A) diagnosed in screening-group participants (CRC incidence of 1.49 per 1000 person-years), 236 (26.4%) were detected by FOB screening, 249 (27.9%) presented after a negative FOB test or investigation, and 400 (44.8%) presented in non-responders. The incidence of cancer in the control group (856 cases, 11% stage A) was 1.44 per 1000 person-years. Median follow-up was 7.8 years (range 4.5-14.5). 360 people died from CRC in the screening group compared with 420 in the control group-a 15% reduction in cumulative CRC mortality in the screening group (odds ratio=0.85 [95%; CI 0.74-0.98], p = 0.026). INTERPRETATION: Our findings together with evidence from other trials suggest that consideration should be given to a national programme of FOB screening to reduce CRC mortality in the general population.

Effect of retesting with dietary restriction in Haemoccult screening for colorectal cancer.

OBJECTIVES: To determine the detection rate, false positive and false negative rates associated with a policy of retesting with dietary restriction after an initial positive Haemoccult screening test for colorectal cancer, in order to compare the cost effectiveness of such a policy with the alternative, in which all subjects with a positive test would proceed directly to diagnostic colonoscopy. METHODS: Over four years in a large randomised control trial in Nottingham 35,260 subjects had a mean of 1.5 screening rounds each at two-yearly intervals, and were followed up for a minimum of 27 months. During this period subjects with positive screening tests were asked to repeat the test with dietary restrictions. Estimates of costs of the initial screening and of diagnostic colonoscopy were used to estimate the cost for each cancer detected by the different policies. RESULTS: 1209 subjects had a positive initial screening test and 1033 (85.4%) completed the retests. Four hundred and ninety nine subjects were investigated and 89 cancers detected. In the 710 subjects with negative retests six interval cancers were diagnosed in the two years after screening. If these had been detected by screening under a policy of immediate colonoscopy, test sensitivity would have been improved from 53.6% to 57.2% (P = 0.02), but the cost for each cancer detected would have increased from pound 773 to pound 1509. CONCLUSION: Retesting with dietary restrictions reduces costs and maximises the benefit of limited colonoscopy resources, but results in a small but significant reduction in test sensitivity compared with a policy for immediate colonoscopy.

Haemoccult screening for colorectal cancer: the effect of dietary restriction on compliance.

The aim of this study was to examine the effect of dietary restrictions on compliance with Haemoccult screening for colorectal carcinoma. One-hundred-and-fifty-three individuals were randomly allocated to perform Haemoccult tests with or without dietary restrictions, over 3 or 6 days. Those who failed to return completed tests within 6 weeks were sent a reminder letter. A small but significant improvement in compliance when testing over a 3-day period has been previously demonstrated but this difference was not seen in this study because of the small sample size. Overall, 72.8% compliance was achieved in those who were not asked to exclude certain foods during the test period compared with 51.8% in those in whom dietary restriction was requested (chi 2 = 7.45, P < 0.01). In a British population compliance with Haemoccult screening is adversely affected by the imposition of dietary restrictions.

Is dietary restriction always necessary in Haemoccult screening for colorectal neoplasia?

Certain dietary constituents may cause guaiac-based faecal occult blood tests to be positive in the absence of blood loss. In a randomized controlled study of Haemoccult screening for the early detection of colorectal cancer, a policy of retesting with appropriate dietary restriction is used to minimize false-positive results. Delay associated with the retesting protocol may cause considerable anxiety. The aim of the study was to determine the likelihood of an initial positive result remaining positive after retesting. One-hundred-and-thirteen of 137 (35.6%) subjects whose initial test was < 5 squares positive remained positive in contrast to 52/59 (88.1%) with > or = 5 squares positive, a significantly higher proportion (P < 0.001). This suggests that if five or more test squares are positive, then dietary interference is unlikely to be responsible. We conclude that, if dietary restriction retesting is practiced, individuals with strongly positive tests may be offered investigation without retesting, thus reducing their delay to further investigation.

Change towards earlier stage at presentation of colorectal cancer.

A study was carried out to investigate the change in stage at presentation of patients with colorectal cancer over 10 years. Cases were identified from the control group of subjects enrolled into a randomized controlled study based on Haemoccult screening for colorectal neoplasia. Of 405 subjects in the control group (presenting with symptomatic colorectal cancer, 206 presented before 1989 and 199 since then. The number of patients with Dukes' stage A carcinoma diagnosed since 1989 rose from 21 (10.4 per cent) to 35 (18.1 per cent); this change occurred for rectosigmoid tumours (9.9 per cent before 1989, 28 per cent after 1989) but not for colonic cancer (10.9 per cent before 1989, 11.5 per cent thereafter). An increase in the proportion of patients with symptomatic early-stage rectosigmoid cancer has been observed in the past 10 years. No such change occurred in those with colonic cancer. This may reflect a change in awareness of te disease and its symptoms by patients and general practitioners.

Faecal occult blood screening for colorectal neoplasia: a randomized trial of three days or six days of tests.

Haemoccult, a guaiac test for faecal occult blood, detects 56-78 per cent of asymptomatic carcinomas when performed over 3 days. In patients with known colorectal cancer the sensitivity of the test for neoplasia is increased by extending the test period to 6 days. We report the first randomized comparison of 3 day with 6 day testing in asymptomatic individuals. 35,184 age and sex matched individuals were randomly allocated to receive Haemoccult over 3 or 6 days. The tests were completed by 10,176 (57.8 per cent) of the 17,616 offered 3 day Haemoccult and 9461 (53.9 per cent) of the 17,568 offered 6 day Haemoccult, a significant decrease in compliance (P less than 0.001). Of the 3 day Haemoccult tests 131 (1.29 per cent) were positive, significantly fewer than the 160 (1.69 per cent) positive tests after 6 day Haemoccult (0.01 less than P less than 0.02). Investigation of subjects with a positive test revealed 20 carcinomas (1.14 per 1000 offered and 1.97 per 1000 completing the test) in the 3 day group and 24 carcinomas (1.37 per 1000 offered and 2.54 per 1000 completing the test) after 6 day Haemoccult tests (0.5 less than P less than 0.7 for those offered the test and 0.3 less than P less than 0.5 for those completing it). After 3 day Haemoccult 112 adenomas in 76 persons were detected (4.31 per 1000 offered and 7.47 per 1000 completing the test). In the 6 day group 123 adenomas in 83 persons (4.72 per 1000 offered and 8.77 per 1000 completing the test) were detected (0.5 less than P less than 0.7 for those offered the test and 0.3 less than P less than 0.5 for those completing it). Large adenomas were found in 27 individuals after 3 day testing (1.53 per 1000 offered the test and 2.65 per 1000 completing it) and in 35 individuals after 6 day testing (1.99 per 1000 offered the test and 3.70 per 1000 completing it) (0.3 less than P less than 0.5 for those offered the test and 0.1 less than P less than 0.2 for those completing it). This study has not demonstrated a significant increase in the yield of neoplasia in asymptomatic subjects offered Haemoccult over 6 days. However there was a significant decrease in compliance and a higher rate of colonscopy in those offered 6 day testing.

Faecal occult blood screening of first degree relatives of patients with colorectal cancer.

A full first-degree family history was taken from 161 patients with colorectal cancer (Group 1) and from a group of 203 subjects previously investigated and found to have no colorectal neoplasia (Group 2). Twenty-six (16%) of patients in Group 1 compared with 23 (11%) in Group 2 had at least 1 first-degree relative with colorectal cancer (p = 0.23). Contact of first-degree relatives was possible in 123 patients in Group 1. Of these, 4 were members of 'cancer families' with 26 available first-degree relatives. The remaining 119 patients had 341 contactable first-degree relatives. They were approached by post and offered faecal occult blood (FOB) screening. One hundred and sixty-two (47%) completed FOB tests of which 12 (8%) were positive. Investigation of these individuals detected 4 adenomas. In the subgroup of 20 patients with 1 or 2 first-degree relatives with colorectal cancer, there were 78 potential relatives of whom 71 were contacted. Thirty-two (45%) FOB tests yielded 1 positive found to have an adenoma. A control group of 332 individuals was selected randomly from general practitioners' lists and offered FOB testing. One hundred and fifty-five (47%) complied of whom 7 (4.5%) were positive. Investigation yielded 1 adenoma. Thirteen of the 26 relatives of the 4 'cancer family' patients were investigated by endoscopy and 2 (15%) had large polyps detected. Although there may be an increased risk of colorectal neoplasia in first-degree relatives of patients with sporadic colorectal cancer, this risk is not sufficiently high to justify separate screening.