B. Hofstad

Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years.

BACKGROUND, AIMS, AND PATIENTS: In a prospective follow up and intervention study of colorectal polyps, leaving all polyps less than 10 mm in situ for three years, analysis of redetection rate, growth, and new polyp formation was carried out in 116 patients undergoing annual colonoscopy. The findings in relation to growth and new polyp formation were applied to 58 subjects who received placebo. RESULTS: Redetection rate varied from 75-90% for each year, and was highest in the rectum and sigmoid colon. There was no net change in size of all polyps in the placebo group, however, polyps less than 5 mm showed a tendency to net growth, and polyps 5-9 mm a tendency to net regression in size, both for adenomas and hyperplastic polyps. This pattern was verified by computerised image analysis. Patients between 50 and 60 years showed evidence of adenoma size increase compared with the older patients, and the same was true for those with multiple adenomas (four to five) compared with those with a single adenoma. The new adenomas were significantly smaller and 71% were located in the right side of the colon. Patients with multiple adenomas had more new polyps at all the follow up examinations than patients with a single adenoma. One patient developed an invasive colorectal carcinoma, which may be evolved from a previously overlooked polyp. Two polyps, showing intramucosal carcinoma after follow up for three years, were completely removed, as judged by endoscopy and histological examination. CONCLUSIONS: The results show that follow up of unresected colorectal polyps up to 9 mm is safe. The consistency of growth retardation of medium sized polyps suggests extended intervals between the endoscopic follow up examinations, but the increased number of new polyps in the proximal colon indicates total colonoscopy as the examination of choice. The growth retardation of the medium sized polyps may partly explain the discrepancy between the prevalence of polyps and the incidence of colorectal cancer.

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.

Growth and recurrence of colorectal polyps: a double-blind 3-year intervention with calcium and antioxidants.

Background: Dietary calcium and antioxidants have been suggested as protective agents against colorectal cancer. This has been supported by animal experimental studies, case control and cohort studies. Materials and Methods: In a prospective intervention study of colorectal adenomas, and intermediary stage in colorectal carcinogenesis, 116 polyp-bearing patients received a placebo-controlled daily mixture of β-carotene 15 mg, vitamin C 150 mg, vitamin E 75 mg, selenium 101 µg, and calcium (1.6 g daily) as carbonate for a period of 3 years with annual colonoscopic follow-up to test if the mixture was able to reduce polyp growth or recurrence. All polyps of <10 mm at enrolment or follow-up were left unresected until the end of the study. Results: 87–91% of the patients attended the annual endoscopic follow-up investigations, and 19% of the patients dropped out of the medical intervention. The rest consumed 85% of the total amount of tablets over the 3 years. The fecal calcium concentration was 2.3–2.7 times higher in patients taking active medication compared to the placebo group. Diet registration showed that, when adding the intake of antioxidants and calcium from diet and intervention, there was a significant difference between the intake of these substances in the active and the placebo group. No difference was detected in the growth of adenomas between the active and the placebo group from year to year and for the total study period. Moreover, there was no effect on polyps of <5 or 5–9 mm, or on polyps in the different colonic segments analyzed separately. A reduced growth of adenomas was found in patients <60 years of age taking active medication (n = 8) compared to those taking placebo (n = 6; mean difference 2.3 mm; 95% CI 0.26–4.36). There was a significantly lower number of patients free of new adenomas in the placebo group compared to those taking active medication as tested by logistic regression and Kaplan-Meier analysis (log-rank test p value 0.035). Subgroup analysis showed that only the group of patients with no family history of colorectal cancer, those with only one adenoma at inclusion, and those <65 years benefitted from the intervention medication. Conclusion: The study did not find an overall effect on polyp growth. Our data, however, may support a protective role of calcium and antioxidants on new adenoma formation.

Does high body fatness increase the risk of presence and growth of colorectal adenomas followed up in situ for 3 years

OBJECTIVE:Obesity is an increasing problem for industrialized nations. The incidence of colorectal cancer has also risen during the last decades. However, information is scarce about the association between the colorectal cancer precursors, adenomatous polyps, and body composition. Our aim was to find out if body fatness is related to the presence of polyps and of growth of adenomas of ≤9 mm observed in situ over 3 yr.METHODS:Twenty-eight outpatients with colorectal polyps and 50–75 yr of age were compared with 34 sex- and age-matched (±5 yr) polyp-free healthy controls. The polyp patients were randomly selected from a double blind 3-yr placebo-controlled endoscopic follow-up and intervention study against growth and recurrence of polyps among 116 polyp-bearing outpatients. Triceps skinfold thickness (TSF) was measured by a Harpenden caliper and total body fat percentage (BF%) by Futrex 5000. Dietary intake was calculated in a 5-day dietary record by weighing. Demograpic data, including smoking and alcohol habits, were registered by an interview and self-administrated questionnaires. Weight and height were measured.RESULTS:TSF and BF% ranked 66% of the individuals into the same quartiles, and 34% were ranked into the adjacent quartiles. The coefficient of correlation between TSF and BF% was highly significant (r = 0.90, p < 0.01, n = 62). TSF, BF%, and body mass index (kg/m2) did not differ between polyp patients and controls in either crude or adjusted analyses. Adenoma growth was, however, highly associated with increasing levels of TSF (p = 0.004), BF% (p = 0.02), and body mass index (p = 0.006).CONCLUSIONS:Our data suggest that high body fatness is a promoter of adenoma growth. Similar results were obtained with the caliper and Futrex 5000, which lends credibility to this study. For repeated documentation, a larger study population should be investigated. To our knowledge, this is the first case-control study to investigate the relationship between body composition and growth of adenoma by follow-up in situ over 3 yr.

Growth of Colorectal Polyps: Recovery and Evaluation of Unresected Polyps of Less Than 10 mm, 1 Year after Detection

BACKGROUND AND METHODS Colonoscopic 1-year control of polyps of less than 10 mm left in situ was carried out in 103 (89%) of 116 originally examined patients. RESULTS Analysis showed an 85% recovery: 91% and 81% for polyps of 5-9 mm and < 5 mm, respectively. The recovery was significantly related to size and localization, whereas the growth rate was inversely correlated to the originally measured diameter. A linear relationship was demonstrated between anus-to-polyp distances 1 year apart, with a normalized agreement index of 0.70. In only 1 of 189 polyps, an increase of diameter to > 10 mm was demonstrated. The 79 new polyps in 52 (50%) of the patients were significantly smaller, more often right-sided, and related to multiplicity of polyps at the initial examination but not to growth of recovered polyps or cleansing status. CONCLUSION An acceptable recovery and growth rate of polyps < 10 mm seems to justify the continuation of the study for the remaining 2 years.

Smoking and colorectal adenomas: a case-control study.

The short-chain fatty acid butyrate is regarded as a regulative agent in haemostasis of mucosal cell turnover. Inhibition of prostaglandin E2 synthesis is particularly involved in this regulation process. In the present study, proliferation was stimulated in colonic biopsies of 12 healthy subjects (age 51.3 years, range 25-81) by incubation with deoxycholic acid (5 micromol/l DCA). The anti-proliferative and cyclo-oxygenase-inhibiting properties of butyrate (10 mmol/l BUT) and of aspirin (555 micromol/l ASA) were investigated. Colonic cell proliferation was determined by bromodeoxyuridine immunohistochemistry. PGE2 release into the incubation medium was measured by radioimmunoassay. Incubation with DCA/ASA, DCA/BUT and DCA/ASA/BUT revealed a significant reduction in crypt cell proliferation as measured by the labelling index of the whole crypt in comparison to incubation with DCA alone (DCA/ASA: 0.14, P < 0.01; DCA/BUT: 0.15, P < 0.05; DCA/ASA/BUT: 0.15, P < 0.05, versus DCA: 0.18). The labelling index for the upper 40% of the crypt was only lower after incubation with DCA/ASA (0.023) compared to DCA (0.028) (P < 0.05). PGE2 release from biopsy specimens was only significantly decreased in the incubation media where ASA was added (DCA/ASA: 29.0 pg/mg mucosa/h, P < 0.005; DCA/ASA/BUT: 31.4 pg/mg mucosa/h, P < 0.01 versus DCA: 56.9 pg/mg mucosa/h). Butyrate and aspirin showed no synergistic effects. The results indicate a normalization of DCA-induced hyperproliferation of colonic mucosa by butyrate, and, even more efficiently, by aspirin. The data support the hypothesis that butyrate and aspirin can act as chemopreventive agents in colon carcinogenesis.

Reliability of in situ Measurements of Colorectal Polyps

A reliable and sensitive in situ method for measuring polyp size is fundamental for growth studies of colonic polyps. A measuring probe inserted through a colonoscope can give a visual assessment of polyp diameter, and from a picture of the polyp the area of the polyp on the picture can be calculated by computerized analysis. To test the reliability and sensitivity of these two in situ measurements, 43 colonic polyps (mean diameter, 8.5 mm; range, 4-20 mm) removed by snare diathermy resection were examined. The maximal diameter was measured, and two Polaroid pictures taken of each polyp. After polypectomy each polyp was subjected to extracorporeal reassessment of diameter and measurement of weight and volume. By computerized analysis of the pictures the following variables were estimated: 1) area of the polyp on the picture; 2) largest diameter; 3) maximum width 90 degrees on the largest diameter; 4) maximum distance from centre of gravity; and 5) minimum distance from centre of gravity. Results showed good correlation between diameter measured in situ and after removal (r = 0.93), diameter raised to the 3rd power and weight (r = 0.93), and also to volume (r = 0.77). Area analysis compared with weight was less good (r = 0.72). A very high correlation was demonstrated between weight and volume (r = 0.99). We conclude that the measurement of diameter in situ with a measuring probe is sensitive and somewhat more reliable than computerized analysis of size. The present 3-year follow-up and intervention study will show which of the two methods is preferable for evaluation of polyp growth.

Does a family history of cancer increase the risk of occurrence, growth, and recurrence of colorectal adenomas?

Background: Familial history of colorectal cancer (FHCRC) is a recognised risk factor for sporadic CRC. The relationship to the growth rate of adenomas is largely unknown. Lifestyle related factors, which may also cluster in families, are also recognised risk factors for adenomas and CRC. Aims: To study the relationships between FHCRC and family history of other cancers (FHOC) among first degree relatives in relation to occurrence, growth, and recurrence of adenomas. Patients and methods: Eighty seven patients with adenomas, participating in a double blind, three year, placebo controlled, endoscopic follow up and intervention study of growth and recurrence of polyps (50% men, 50–76 years). Polyps >9 mm were removed whereas the remainder and newly discovered polyps <10 mm were left in situ for three years before removal and histological diagnosis. Data were collected by means of dietary records, interviews, and questionnaires. Results: The adenoma cases with FHCRC had a fourfold higher risk of adenoma growth. In contrast, no significant association was found for adenoma recurrence. FHOC was not significantly related to increased risk of growth or recurrence. Family history showed no significant association with the risk of baseline adenoma occurrence. Adjustment for CRC risk factors, also known to cluster in families, did not alter the results. Conclusions: FHCRC seems to be a strong risk factor for adenoma growth, but not for the earlier phases of CRC development such as the initiation of adenomas.

Current diet and colorectal adenomas: a case-control study including different sets of traditionally chosen control groups.

High intake of fat and a low intake of foods rich in antioxidants and fibre are suggested to be associated with risk of colorectal adenomas. Inconsistency may, however, be due to dietary assessment problems or differences in the identification of cases and controls. We have compared 87 adenoma cases aged 50–76 years with 35 healthy controls and 35 ‘hospital’ controls. All the controls were matched for sex and age (±5 years) and proven to be free of polyps. Current habitual diet was measured by a 5‐day dietary record by weighing. Regarding the intakes of vegetable fat, protein, cholesterol, vitamin A, total vitamin D, edible fats, coffee and fish and fish products, the outcomes of the analysis depended upon the source of controls. However, an increased adenoma risk compared with either set of controls related to a low consumption of vegetables, cereals, iron, vitamin C and fibre and a high intake of total fat was found. This is suggestive of substantial differences, since bias due to abdominal symptoms, the dietary records or an inappropriate choice of controls, would have affected the estimations. The findings give further strength to the role of these dietary factors in the formation of precancerous lesions in the large intestine.

Inter-Endoscopist Variation in Polyp and Neoplasia Pick-up Rates in Flexible Sigmoidoscopy Screening for Colorectal Cancer

Background: The Norwegian Colorectal Cancer Prevention study is an ongoing flexible sigmoidoscopy (FS) screening trial for colorectal cancer. Twenty‐one thousand average‐risk individuals, aged 50–64 years, living in two separate areas in Norway were randomly drawn from the Population Registry and invited to once‐only screening flexible sigmoidoscopy. Examinations were performed over 3 years, at 2 centres, by 8 different endoscopists, using the same type of equipment. The aim of the present study was to investigate possible differences between endoscopists in detecting individuals with polyps, adenomas and advanced lesions (adenomas with severe dysplasia and/or villous components and/or size larger than 9 mm and carcinoma) in flexible sigmoidoscopy screening. Methods: The present trial comprises data from 8822 individuals, aged 55–64 years, who have undergone a flexible sigmoidoscopy. In the study period, all lesions detected by the different endoscopists were registered. Tissue samples were taken from all lesions detected. Results: Detection rates varied significantly between endoscopists, ranging from 36.4% to 65.5% for individuals with any polyp, from 12.7% to 21.2% for any adenoma and from 2.9% to 5.0% for advanced lesions. In a multiple logistic regression model, the performing endoscopist was a strong independent predictor for detection of individuals with polyps (P < 0.001), adenomas (P < 0.001) and advanced lesions (P = 0.01). Conclusion: Detection rates for colorectal lesions vary significantly between endoscopists in colorectal cancer screening. Establishing systems for monitoring performance in screening programmes is important. Supervised training and re‐certification for endoscopists with poor performance should be considered.