Results

In total 960 (2.1%) people required colonic investigation following their first screen. Following rescreening 1090 (1.2%) tests were positive; 1778 people (4.0% of those accepting screening at least once) underwent examination of their rectum and colon on one or more occasions. In this group 1474 colonoscopies and 738 DCBEs were done.

During the course of the trial, 236 cancers were detected by screening, 249 interval cancers presented, 400 cancers were diagnosed in non-participants, and 856 presented in the control group. A further eight cancers in the study group were diagnosed during endoscopic surveillance of a screen detected lesion.

The interval cancers included 13 following a positive test (two investigated by colonoscopy and six by DCBE where no abnormality was found, and five where further investigation was refused). This suggests a sensitivity for colonic investigation, based on interval cancer rates, of 236/(236+6+2) = 96.7% (95% CI 94.5–99.0%). Of the eight interval cancers following a positive test and negative investigation (stage A=0, B=1, C=3, D=4), none presented in the first year, six in the second year, and one in the third year. The remaining case presented 13 years following a positive test. Colonoscopy missed two cancers—one in the sigmoid colon, the other in the caecum. All six cancers missed by DCBE were located proximal to the hepatic flexure. Of these six, barium enema was the primary means of investigation in four; in the other two, it was carried out following an incomplete colonoscopy.

Table 1 shows the stage distribution of the interval and control group cancers. The interval group (n=249) had a higher (but not significantly) proportion of stage A tumours (16% versus 11%, p=0.05) than and a similar proportion of advanced (stage C, D, and unknown) tumours (54% versus 56%, p>0.1) to the control group (n=856). However, survival was better for the interval cancers (p<0.01); this advantage is reduced but remains significant if the stage distribution is taken into account (p=0.02).

There were no complications of DCBE but seven (7/1474 = 0.5%) complications of colonoscopy (five perforations, one major bleed, one snare entrapment), of which six required surgical intervention. None of these patients died and there were no colonoscopy related deaths. No patients died within 30 days of colonic investigation who were not being treated for detected colorectal neoplasia.

Five patients died within 30 days (postoperative days 0, 1, 4, 9, 14) of surgery for screen detected colorectal cancer or adenoma (adenoma=1, cancer stages A=0, B=1, C=2, D=1). Cause of death in these cases was myocardial infarction in one, anastomotic leak in one, pulmonary embolus in two, and carcinomatosis in one. Preoperative investigation revealed metastatic disease in two further patients who died within 30 days of diagnosis without having surgery (stage D=2). Thirty six patients died after 30 days but within two years of surgery (26 from recurrent colorectal cancer, four from other malignancy, three from cardiovascular causes, one from chronic obstructive pulmonary disease, and two from degenerative neurological disease). Of this group of 36, two had had screen detected benign adenomas and four had had stage A cancers. The cause of death in all six was considered on death review not to be related to colorectal cancer (three, other malignancy; three, cardiovascular). Clearly, all 43 patients mentioned could not be considered to have benefited by the earlier detection of their colorectal cancer. However, of this group of 43, only the six patients with adenomas or stage A cancers (who died of unrelated other conditions within two years of detection of the tumour by screening) would probably never have presented with their tumour during their remaining lifetime. In other words, only six patients would have probably been “overdiagnosed”.

Discussion

This study has previously reported a statistically significant 15% reduction in colorectal cancer mortality by FOB screening but no reduction in all cause mortality.10 This supports the findings of five case control studies5-9 and two other randomised controlled trials10 ,12; and is similar to the findings of a meta-analysis of the six controlled trials.13 The case for a national screening programme is currently being considered by the Department of Health’s National Screening Committee. However, opponents of FOB screening point to the financial costs and psychological risks. Both issues have been prospectively addressed in the setting of this trial (M Parker, personal communication),19 but Ahlquist has raised other areas of concern.16

Patients with colorectal cancer who complete a FOB test which is negative may be falsely reassured and delay presentation with symptoms. If this were the case, we should expect a less favourable stage distribution and worse survival in this group compared with controls; the opposite was, in fact, observed, both in this and in the Danish trial.12

It might also be argued that, had the tumours missed by colonic investigation been detected at screening, they could have been treated endoscopically, potentially avoiding the need for surgery. This is unlikely as none of the interval cancers was at stage A while seven of the eight were stage C or D when subsequently presenting with symptoms. This failure of colonoscopy and/or barium enema equates to a sensitivity for investigation of 96.7%, similar to the findings of a recent large US study.20 It is not possible to quantify the relative sensitivities of colonoscopy versus DCBE in our study. However, as in the study of Rex et al,20 we have found that DCBE was more likely to miss cancers than colonoscopy.

Colonoscopy is potentially hazardous.21 In this trial, six major complications of colonoscopy (0.5%) occurred but with no mortality. Five of the complications were the result of a therapeutic intervention and one occurred in a diagnostic procedure. The latter was a retroperitoneal perforation in a segment of severe diverticular disease and this patient did not require surgical intervention. This paper addresses only those colonic evaluations carried out as a direct result of a positive FOB test. It should be emphasised that any colorectal cancer screening programme, through the detection of adenomas, will generate a substantial number of follow up surveillance colonoscopies. Although there was no mortality, the morbidity does highlight the need for careful audit of colonoscopy performance, particularly if national screening were to be introduced. This is reinforced by the recent highly publicised failings in the cervical cancer screening programme. A recent review of this programme has highlighted the need to emphasise four areas: (1) the aim of the screening test (cervical screening is not a test for cancer but for abnormal cells that might lead to cancer); (2) the fallibility of the test (it is not 100% accurate); (3) the need for reporting symptoms irrespective of the result of the screening test (abnormal bleeding); and (4) the screening programme is effective (cervical screening prevents up to 3900 deaths per year).22 A future national colorectal cancer screening programme must address and emphasise these same four issues.

There was no serious morbidity and no mortality in relation to DCBE, acknowledged to be a safer procedure than colonoscopy. As regards cardiorespiratory (or any other) mortality relating to sedation at colonoscopy, no patients (who did not have colorectal cancer) died within 30 days following any colonic investigation. How to investigate individuals with a positive FOB test (colonoscopy versus DCBE and flexible sigmoidoscopy) has been a key question for the National Screening Committee to answer. It is clear that, at present in the United Kingdom, there is insufficient availability of both colonoscopy and DCBE—the introduction of a screening programme will, of necessity, address this. In due course, rapid developments in computed tomographic colography (“virtual colonoscopy”)23 may supplant these diagnostic procedures.

It is possible that certain individuals with screen detected cancers would have died of other disease before their tumour declared itself. These individuals will have suffered “unnecessary” investigation and surgery and needless anxiety. It is difficult to quantify this overdiagnosis but it may be reflected in 30 day mortality for those with screen detected cancers. Five patients died a median of four (range 0–14) days postoperatively, one of whom had had an anastomotic leak. Of those dying after 30 days but within two years, only four had stage A disease, three of whom died of other malignancy. It would seem that the scale of overdiagnosis is small.

We have shown and quantified some of the physical risks of screening in this paper while the financial costs of the study have been previously addressed.19 A new method of expressing the costs and benefits of a medical intervention has been recently described. This is the number that need to be treated (NNT), and the number that need to be harmed (NNH), to produce a given beneficial outcome. This concept can be adapted to cancer screening24to inform the increasingly visible debate on rationing. We have previously reported that 44 838 individuals have accepted at least one offer of screening; and that, at median follow up of 7.8 years, there were 60 fewer deaths attributed to colorectal cancer in the group offered screening compared with controls.11 This report has highlighted the six individuals who have been sufficiently harmed by the process of investigation to require surgical intervention. Therefore, in this study, the number that needed to be screened (over 7.8 years) to prevent one colorectal cancer death was 747 (44 838/60) (NNT variant). Conversely, one person will be sufficiently harmed by the process of investigation to require surgical intervention for every 10 (60/6) colorectal cancer deaths prevented (NNH variant). The NNT variant for the Danish12 and Minnesota10trials was 470 (20 672/40) over 10 years and 360 (14 034/39) over 13 years respectively.

The type of adverse consequences discussed are common to any cancer screening programme. However, they must be recognised (by both the medical profession and, more importantly, by the population as a whole) as being implicit to a programme whose overall effect is beneficial. They must also be minimised (and be seen to be minimised) by close attention to quality control and audit. Only then will public confidence, essential to the success of any cancer screening programme, be maintained. The importance of this area needs considerable emphasis.

The accumulating evidence is that FOB screening reduces colorectal cancer mortality. Serious consideration should be given to the development of a national colorectal cancer screening programme based on FOB testing.