N. C. Armitage

RANDOMISED, CONTROLLED TRIAL OF FAECAL OCCULT BLOOD SCREENING FOR COLORECTAL CANCER: Results for First 107 349 Subjects

To assess the effectiveness of screening by faecal occult blood tests, 107,349 people without symptoms of colorectal disease identified from general practitioner records have been randomly allocated to test and control groups. 53,464 test subjects were invited to carry out the screening test; 27,651 (53%) of the 52,258 who received the tests did so. Further investigation of the 618 (2.3%) with positive tests showed 63 cancers (52% stage A) and 367 adenomas (266 subjects). Rescreening of subjects with negative results every 2 years (9510 first rescreen, 3639 second) has shown a significant fall in the rate of positive results (1.7% of 7344; 0.3% of 2906). Cancers have also been diagnosed in 20 subjects presenting in the interval between a negative test and rescreening, and in 83 non-responders. The incidence of cancer in the control group (123 subjects; 10.6% stage A) was 0.72 per 1000 person-years. Cancers detected by screening were at a less advanced pathological stage, but it is too early to show any effect of screening on mortality from colorectal cancer.

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.

Enhanced expression of the complement regulatory protein CD55 predicts a poor prognosis in colorectal cancer patients

This study prospectively correlated the level of expression of CD55 on tumours with 7-year survival in 136 colorectal cancer patients. Patients with tumours expressing high levels of CD55 had a significantly worse survival (24%) than patients with low CD55 levels (50%, p<0.02). A similar difference was seen for patients (Dukes B or C) with a high risk of recurrence (29% vs 58%, p<0.05). Furthermore, there was a progressive deterioration in prognosis with increasing antigen expression (p=0.01). It remains unclear if CD55 is overexpressed by tumours to protect them from complement or if it is related to the recent observation that CD55 is a ligand for the T-cell activation antigen CD97. However, it is a marker of aggression, as colorectal cancer patients whose tumours overexpress CD55 have a significantly reduced 7-year survival.

Preoperative carcinoembryonic antigen is related to tumour stage and long-term survival in colorectal cancer.

Evidence as to the value of preoperative carcinoembryonic antigen (CEA) in guiding treatment for patients with colorectal cancer is conflicting. The aim of this prospective study was to investigate the value of preoperative CEA in predicting tumour factors of proven prognostic value and long-term survival in patients undergoing surgery for colorectal cancer. Preoperative serum CEA, tumour ploidy, stage and grade were ascertained in 277 patients undergoing colorectal cancer surgery. This cohort of patients were followed up for a minimum of 5 years, or until death, in a dedicated colorectal clinic. Patients with an elevated CEA had a 5 year survival of 39%. This increased to 57% if the CEA was normal (P=0.001). The proportion of patients with a raised CEA increased with a more advanced tumour stage (P < 0.000001) and a poorly differentiated tumour grade (P < 0.005). Once stage had been controlled for, CEA was not a predictor of survival. No relationship between tumour ploidy and CEA was found. In conclusion, a raised preoperative serum CEA is likely to be associated with advanced tumour stage and poor long-term survival, compared with patients with a normal value.

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.

Five-year prospective study of DNA tumor ploidy and colorectal cancer survival†

Background. Retrospective studies have suggested that DNA tumor content (ploidy) has a significant effect on survival. This group has reported, prospectively, that among patients who had colorectal resections for carcinoma, the 2‐year tumor recurrence rate was significantly greater for patients with aneuploid tumor than for those with diploid tumors. This paper reports the 5‐year survival rates of this cohort of patients.

Folate Metabolism Polymorphisms Influence Risk of Colorectal Adenoma Recurrence

Folate intake is inversely related to risk of developing colorectal neoplasia. Associations between risk of colorectal neoplasia and polymorphisms in genes coding for enzymes involved in folate metabolism have also been reported, suggesting a relationship between genotype and development of colorectal neoplasia. To further investigate the effects of folate metabolism genotypes on colorectal neoplasia, we genotyped 546 patients participating in a randomized controlled trial of folate supplementation for the prevention of colorectal adenoma recurrence. A significantly reduced risk of recurrence was observed in patients heterozygous for the MTRR A66G polymorphism [relative risk (RR), 0.64; 95% confidence interval (95% CI), 0.46-0.90] or heterozygous for the MTHFR A1298C polymorphism (RR, 0.71; 95% CI, 0.52-0.97). Furthermore, a significant reduction in recurrence risk was seen in MTRR A66G heterozygotes who received folate supplements but not in those who did not receive folate. Patients heterozygous for the MTHFR C677T polymorphism had a nonsignificant risk reduction (RR, 0.92; 95% CI, 0.69-1.23), as did patients with one or two variant alleles for the MTR A2756G polymorphism (RR, 0.82; 95% CI, 0.60-1.12). No influence on recurrence risk was observed for the TSER, TSER 3R G>C, and TS 1494del6 variants. These findings provide additional support for the hypothesis that germ line variants in folate metabolism genes influence the development of colorectal adenomas. (Cancer Epidemiol Biomarkers Prev 2006;15(9):1607–13)

V-Y advancement flap for treatment of fistula-in-ano

AbstractPURPOSE: The management of high fistula-in-ano presents a difficult surgical challenge. Laying open of high transsphincteric, intersphincteric, and suprasphincteric fistulas is associated with incontinence. Mucosal advancement flap can be technically difficult and is associated with ectropion and incontinence. We report a new technique for the treatment of fistulas, which may eliminate these problems. PATIENTS AND METHODS: Between 1997 and 2002, 18 patients (13 males), median age 46 (range, 25–64) years with high fistula-in-ano were treated. There were ten transsphincteric, four intersphincteric, and four suprasphincteric fistulas. In all patients, perianal sepsis was allowed to resolve completely with a drainage seton before definitive surgery. The surgical technique used involved core fistulectomy, curettage of any cavity, closure of the defect in the internal anal sphincter, and a V-Y advancement buttock flap to cover the internal opening, leaving the site of the external opening for drainage while preserving both internal and external sphincters. Outcome was assessed in terms of healing and continence. RESULTS: Most patients were discharged from the hospital within 48 hours. Median follow-up was 19 (range, 3–60) months. There were three patients who failed to heal. Of these, two underwent repeat surgery and healed. Two further patients had recurrent fistulas, both of whom continued with conservative treatment. Overall, 15 of 18 (83 percent) patients experienced healing of their fistula. Continence was preserved in all patients. CONCLUSION: This procedure is easy to perform, healing is rapid, and it appears to be effective in curing fistula-in-ano while preserving both external and internal anal sphincters.

Genetic Variants of UGT1A6 Influence Risk of Colorectal Adenoma Recurrence

Purpose: The UDP glucuronosyltransferase 1A6 (UGT1A6) and cytochrome P450 2C9 (CYP2C9) enzymes participate in the metabolism of nonsteroidal anti-inflammatory drugs, endogenous substances, and carcinogens. Functional polymorphisms of UGT1A6 (T181A and R184S) and CYP2C9 (R144C and I359L) have been reported to modify the protective effect of aspirin on colorectal adenoma risk. We aimed to further investigate the effect of these genetic variants on the development of colorectal neoplasia. Experimental Design: We examined the relationship between UGT1A6 and CYP2C9 genotype and colorectal adenoma recurrence in 546 patients participating in a randomized placebo-controlled aspirin intervention trial. Results: Although colorectal adenoma recurrence was not significantly influenced by CYP2C9 genotype, carriers of variant UGT1A6 alleles were at significantly reduced risk of colorectal neoplasia recurrence [relative risk (RR), 0.68; 95% confidence interval (95% CI), 0.52-0.89]. This risk reduction was also evident when the analysis was confined to advanced neoplasia recurrence (RR, 0.71; 95% CI, 0.47-1.09). When patients were stratified by genotype and aspirin intervention, those with variant UGT1A6 alleles were at reduced recurrence risk irrespective of whether they received aspirin or placebo (RR, 0.62; 95% CI, 0.42-0.92 and RR, 0.63; 95% CI, 0.44-0.91, respectively). Conclusions: These findings confirm that UGT1A6 variants influence colorectal carcinogenesis independent of aspirin intake and suggest that they may have clinical value in secondary prevention programs for patients diagnosed with colorectal adenoma.

Endoscopic screening of relatives of patients with colorectal cancer

Background—The risk of colorectal cancer is higher among relatives of those affected. The neoplastic yield reported from screening such individuals varies enormously between studies and depends on the age and strength of the family history of those screened. Aims—To ascertain the neoplastic yield of endoscopic screening of first degree relatives of patients with colorectal cancer by age and familial risk. Subjects—A total of 330 individuals with a family history of colorectal cancer. Method—Endoscopic screening conducted according to a protocol. Results—Adenomas were found in 12%, and adenomas larger than 1 cm in 8%, of “high risk” individuals screened primarily by colonoscopy. Of those with neoplasia, 26% had lesions at or proximal to the splenic flexure. Neoplasia was found in 9.5% of individuals at lower familial risk, screened primarily by 60 cm flexible sigmoidoscopy, 4% of whom had neoplasia larger than 1 cm in size or cancer. Neoplastic yield was greatest in the fourth and fifth decades in those at highest risk, but increased with age in those at lower risk. Conclusions—For individuals with two or more first degree relatives, or relatives who have developed colorectal cancer at a young age, colonoscopy appears to be the only satisfactory method of screening, but 60 cm flexible sigmoidoscopy may be useful in those at lower levels of risk.