M. H. E. Robinson

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.

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.

Risks, costs, and compliance limit colorectal adenoma surveillance: lessons from a randomised trial.

BACKGROUND AND AIMS In the USA and many other countries, endoscopic surveillance of colorectal adenoma patients is now widely practised. However, the optimal frequency and mode of such surveillance are not yet established. The aim of this trial was to compare surveillance at one, two, or five year intervals using either flexible sigmoidoscopy or colonoscopy. METHODS Analysis of a randomised trial of flexible sigmoidoscopy and colonoscopy over one, two, or five years after stratification for “high” or “low” risk of recurrent adenomas. The trial started in 1984. RESULTS A total of 776 patients were stratified into “high” (n=307) and “low” (n=469) recurrence risk groups and randomised to flexible sigmoidoscopy or colonoscopy at varying intervals. Only 81 recurrent adenomas (30/81 were >1 cm in diameter) were detected in the 2307 person years of follow up within the surveillance study. Adenoma recurrence was significantly higher in the high risk group (relative rate 1.82; 95% confidence interval 1.2–2.9) but recurrence rates per 1000 person years were low and not significantly different in those surveyed by colonoscopy or flexible sigmoidoscopy. Loss to follow up was greatest in those having an annual examination compared with two or five yearly surveillance examinations. Despite surveillance, invasive cancer developed in four patients compared with an expected value of 9.12 for the general population in England (p=0.10); of these four patients who developed cancers, only one was detected by surveillance examination. CONCLUSIONS Adenoma recurrence rates were much lower than expected in both high and low risk groups. This suggests that endoscopic surveillance should be targeted at high risk groups. A surveillance interval of five years was as effective as shorter intervals in terms of cancer prevention, and was associated with similar compliance to two yearly examinations.

Psychiatric morbidity and screening for colorectal cancer

Background: Several studies have shown that faecal occult blood (FOB) screening reduces mortality from colorectal cancer. However, concern has been expressed that health screening may have adverse psychological effects, particularly for the group returning false positive tests. Objectives: To evaluate any adverse psychological effects associated with faecal occult blood screening. Setting: Randomised controlled trial of faecal occcult blood screening for colorectal cancer. Methods: Psychiatric morbidity was measured, using the general health questionnaire (GHQ) before and 3 months after the offer of screening for colorectal cancer with FOB testing. Scores were related to acceptance of the screening test. A smaller cohort, who had returned positive FOB tests, had anxiety levels measured, using the Spielberger anxiety inventory (SAI), at different times during screening, investigation, and follow up. Results: A GHQ was sent to 2184 subjects before the offer of screening, and 1541 (70.6%) were returned. Of the 1693 subjects offered the GHQ 3 months after the offer of screening, 1303 (77%) returned it. A GHQ score of 5 or more, indicating possible psychiatric morbidity, was present in 454 subjects (29.5%) before screening and in 386 (29.6%) subjects 3 months after screening (NS). Of the 454 subjects who scored 5 or more, 241 (53.1%) accepted screening and 213 (46.9%) refused. A total of 1081 subjects scored less than 5, and of these 521 (48.2%) accepted screening and 560 (51.8%) refused (NS). Anxiety scores were measured in 100 test positive patients and were highest after notification of a positive test and before investigation by colonoscopy. In patients with false positive results, scores fell the day after colonoscopy and remained low 1 month later. Conclusions: The receipt of a screening test does not cause sustained anxiety and the existence of psychiatric morbidity is not a factor affecting a persons decision to accept or refuse a screening test for colorectal cancer.

Chemical and immunological testing for faecal occult blood in screening subjects at risk of familial colorectal cancer.

BACKGROUND: People with a family history of colorectal cancer have an increased risk of the disease themselves. Many centres are advocating family history screening by endoscopy. AIMS: The performance of chemical and immunological faecal occult blood tests (Haemoccult and Hemeselect) in 212 subjects with a family history of colorectal cancer was assessed. RESULTS: Both Hemeselect and Haemoccult were positive in the only patient with colorectal cancer. Hemeselect was more sensitive than Haemoccult for adenomas (40% compared with 20%) (adenomas larger than 1 cm 75% compared with 50%). No additional abnormality was detected by the addition of Haemoccult or Hemeselect to 60 cm flexible sigmoidoscopy in screening people at lower levels of familial risk. A false positive rate of 16% for Hemeselect resulted in a high proportion of additional colonoscopies in this group. CONCLUSIONS: At present faecal occult blood tests are not sufficiently sensitive or specific to replace endoscopy in screening people at risk of familial colorectal cancer.

Fecal α1-antitrypsin detection of colorectal neoplasia

Fecal α1-antitrypsin measurement may be of value for the detection of coloreactal neoplasia and is compared with the HemoQuant test in 119 subjects with either a screen-positive Hemoccult result (N=78) or iron-deficiency anaemia (N=41). Nineteen patients were found to have coloreactal cancer, 35 had colorectal adenomatous polyps, 5 had inflammatory bowel disease, and 60 had no detected cause of occult blood loss. Of the cancer patients, 63% (12/19) were detected by fecal α1-antitrypsin, and 63% (12/19) by HemoQuant. Of the adenomas >1 cm in diameter 33% (7/23) were detected by fecal α1-antitrypsin and 26% (6/23) by HemoQuant. There was a poor correlation between fecal α1-antitrypsin, and HemoQuant results for colorectal cancers (r=0.37,P>0.05), and combining the tests, the sensitivity for colorectal cancer was incerased to 84% (16/19). Fecal proteins loss, as measured using α1-antitrypsin, appears to involve largely different mechanisms from that of blood loss from colorectal cancers.

HOMOGRAFT REPLACEMENT OF THE AORTIC VALVE: Immediate Results and Follow-up

Abstract Homograft replacement of the aortic valve was performed on 146 patients between 1964 and December, 1966. An additional surgical procedure was necessary in 50 patients: mitral valvotomy in 25, repair or replacement of the mitral and tricuspid valves in 22, and closure of a ventricular septal defect in 3. Mortality during the initial hospital admission was 24%. 101 patients are alive one to four years after surgery. Postoperative aortic regurgitation developed in more than half the patients but was usually trivial. It was of haemo-dynamic importance in 18 patients, 7 of whom are controlled on medical treatment. There have been no cases of systemic embolism, haemolytic anaemia, or sudden death. Of the 109 patients discharged from hospital with aortic homograft valves the result is considered excellent in 35, good in 38, satisfactory in 11, and poor in 10. Prosthetic replacement of the graft has been successfully performed in 5 patients. There have been 10 deaths since discharge from hospital; aortic regurgitation and infective endocarditis were the principal causes of late deaths.

Cell kinetics of the in vitro metaphase arrest technique and the clinical applications

The in vitro metaphase arrest technique (crypt cell production rate-CCPR) has been used to measure human rectal mucosal proliferation. Study of preincubation times, dose response curves and lag phases suggest that a concentration of vincristine of 5 μg/ml and 16 hour preincubation with time point increments between 25 and 125 minutes give optimal conditions for measuring rectal mucosal proliferation. Twenty individuals had rectal CCPR repeated without intervention of any kind. Close correlation was found between the two values (r = 0.89 and P = 0.0001). The effect of polyethylene glycol bowel preparation was also studied in 35 subjects. There was good correlation (r = 0.66, P = 0.007). There was close correlation between rectal and caecal CCPR as measured in 20 patients who had colonoscopy (r = 0.72, P = 0.0003). The in vitro metaphase arrest technique is a useful parameter of rectal mucosal proliferation and may be used with confidence in a number of different clinical situations.