Results

Of the 1693 patients who were entered into the study, 1074 were men and 619 were women, with a mean age of 56 years (range 40–69) (table 1). Of these patients, 979 were followed up for more than 10 years whereas the mean follow up for the group was 10.5 years. Of interest is the fact that 1264 (74%) subjects had a follow up TCE in the period 1992–1996 and among them 669 (40%) in 1995–1996. For 237 subjects, follow up ended with a TCE.

A total of 165 patients were followed until death. Forty eight patients (2.7%) were lost to follow up and were included in the persons/years at risk until the last known alive date. All cases contributed individually to the persons/years of follow up for a total of 14 211. At the time of enrollment, 721 patients (43%) had adenomas of 0.5–0.9 cm and 972 (57%) had an adenoma ⩾1 cm (624 with adenomas ⩾1.5 cm). Two hundred thirty three patients (14%) had adenomas with high grade dysplasia.

Six colorectal cancer cases (four in males, two in females) at various stages were observed during the study (table 2): one at 29 months from the index examination, the others at five, seven, eight, and 10 years. Three patients with cancer were dead at the time of follow up, at 29 months (one case in the caecum) and at five years (two cases, one in the caecum and one in the rectum). Of the three colorectal cancer cases excluded as missed lesions because they occurred within two years of the index examination, one was diagnosed at 13 months (sigmoid), one at three months (sigmoid), and one at eight months (descending colon; deceased).

Cases expected in the reference general population were 17.7 versus six in our study. The overall incidence ratio was 0.34 (CI 0.23–0.63; p<0.01): 0.31 in males (CI 0.20–0.69; p<0.05) and 0.41 in females (CI 0.22–4.00; NS) (table 3). Incidence ratios were also calculated for the size of adenomas: 0.13 (CI 0.08–0.48; p<0.05) for patients with adenomas 5–9 mm and 0.49 (CI 0.30–1.25; NS) for patients with adenomas more than 1 cm; subject age at enrollment: 0.43 (CI 0.23–5.00; NS) for ages 40–54 and 0.30 (CI 0.20–0.67; p<0.05) for ages 55–69.

Discussion

A prospective clinical trial (NPS) reported a lower than expected incidence of colorectal cancer following removal of adenomatous polyps. The authors concluded that their results supported the view that colorectal adenomas progress to adenocarcinomas, and also that the current practice of searching for and removing adenomatous polyps prevents colorectal cancer.1 The report provided evidence in support of our belief in the concept of adenoma to carcinoma progression. The study also suggested that the current practice of removing adenomas is an effective prevention strategy. The Italian multicentre collaborative study was organised to test if this approach was effective in clinical practice.

The Italian study obtained data from a group of clinical gastroenterologists practising at several centres throughout the country, representing the usual busy clinical schedule of gastrointestinal endoscopy units. It was striking that the reduction in the incidence of colorectal cancer in their clinical environment closely approximated the reduction in incidence observed in the prospective clinical trial conducted by the NPS. In fact, our results support the suggestion of the NPS that their approach can be effective in the control of colorectal cancer in clinical practice. Furthermore, our data agree closely with the US NPS data in which five asymptomatic early stage cancers were observed compared with 20.7 expected in a general population reference database (SEER), with an incidence reduction of 76% in 8401 person/years of follow up. The baseline characteristics of our Italian cohort were similar to those of the US NPS in terms of multiplicity and histology of adenomas, and male/female ratio, but only patients with adenomas ⩾0.5 cm were included.

In our series, six colorectal cancer cases were found at follow up (table 2). Mortality from cancer was probably due to missed lesions during the index examination (case Nos 4, 5, and 6): in case No 5, several rectal polyps were removed during one endoscopic session subsequent to the index examination but the patient did not comply with the six month scheduled recall, dying five years later with Dukes' D cancer. The two other cases underwent several colonoscopies (four and three, respectively) and cancer was diagnosed five years later (case No 4) and 2.5 years later (case No 6). The other cases were observed in patients at high risk who did not undergo follow up colonoscopy surveillance.

Despite the occurrence of six cancers, a significant reduction (odds ratio 0.34) in the incidence of colorectal cancer was observed in our cohort with respect to the general population (table 3).

We compared the risk of colorectal cancer in this cohort with the risk expected in the general population of similar age and sex as our cohort. Comparison with a general population provides a conservative estimate of risk because, as shown in a study performed by Atkinet al at St Mark's,16 adenoma patients without polypectomy intervention have twice the risk for subsequent colon cancer as the general population. Atkinet al further identified a subgroup of patients with adenomas >1.0 cm, or with tubulovillous or villous adenomas who had a 3.6-fold increased risk of colon cancer. Our study was restricted to patients with at least one adenoma of >0.5 cm but 57% had an adenoma of >1.0 cm, the high risk category in Atkin's paper. If we reduce the risk by 10% to account for exclusion of high familial risk patients, and increase the risk to the general population to 3.6, as in Atkin's study, for the 57% of our patients with adenomas >1.0 cm, we estimate 32.7 colorectal cancers would have occurred in our cohort if no polypectomy intervention had occurred. The revised standardised incidence rate would be 6/32.7 or 0.18.

Reduction in the incidence of colorectal cancer following polypectomy has direct relevance to general population screening. Adenomatous polyp is the most common finding in patients with a positive faecal occult blood test (FOBT) or sigmoidoscopy.

Four prospective FOBT17-20 trials and two sigmoidoscopy case control studies2 ,3 demonstrated a reduction in mortality for colorectal cancer. The reduction in mortality observed in the FOBT trials was 15–33%, the greatest reduction being seen in the Minnesota trial, in which a sensitive test was offered every year. The reduction in mortality was a result of identifying and treating earlier stage cancers by colonoscopy in patients with a positive FOBT. As noted in the UK trial, many adenomatous polyps were identified as a result of screening.19 We would expect a second, later effect on mortality as a result of a reduction in the incidence of colorectal cancer following removal of adenomas in these patients. This would make screening more cost effective. A reduction in incidence is being reported from the Minnesota trial as a result of polypectomy.21 Additional studies have been reported22 ,23 or are in progress (prostate, lung, colon, and ovarian screening trial—PLCO24; National Screening Colonoscopy Trial; Once offered Sigmoidoscopy Screening Trial25) addressing the question of colorectal cancer control through an incidence reduction effect on mortality rather than only finding early stage cancers through screening.

In conclusion, our data support the concept of the adenoma-carcinoma sequence as the major pathway of colon carcinogenesis. In addition, we have demonstrated that intervention in this pathway in clinical practice has the potential to reduce the incidence of colorectal cancer. The magnitude of this reduction was similar to that seen in the National Polyp Study. Our study demonstrates that it is possible to achieve this benefit in general clinical practice.