Thirty-day mortality after surgery for colorectal cancer in Denmark.

OBJECTIVE: This study aimed to estimate the 30-day mortality after colorectal cancer (CRC) surgery in Denmark. Mortality was compared to other studies, and between departments, unadjusted and adjusted for case-mix. MATERIALS AND METHODS: All patients in Denmark with a first-time colorectal adenocarcinoma operated between 1 May 2001 and 31 December 2002 were eligible, 5187 patients were included. Mortality was adjusted for age, sex, urgency, tumour location, Dukes' stage and ASA-score. RESULTS: The 30-day mortality in Denmark after CRC-surgery was 9.9%. Adjusted for case-mix, four departments had significantly higher mortality than average. The variation between the 44 departments was significant both for radically operated (P = 0.02) patients and for all operated patients (P = 0.01). CONCLUSION: The 30-day mortality in Denmark seems to be higher than in studies from other countries, but the lack of comparable nationwide studies makes it difficult to evaluate. To uncover the reasons for the departments to diverge significantly from average, further studies are needed.

Dietary patterns and the risk of colorectal adenoma recurrence in a European intervention trial.

The relations between individual foods and nutrients to colorectal tumours are conflicting. Few studies have taken into account the interdependence between individual components of diet and their possible interactions. The aim of the study was to examine the associations between dietary patterns and the risk of colorectal adenoma recurrence in the European fibre-calcium intervention trial. Among the 640 patients with confirmed adenomas at the index colonoscopy, 592 had an initial dietary assessment using a diet history questionnaire. The present analysis was restricted to 277 men and 165 women without history of adenoma prior to the index colonoscopy and who completed the study. The main end point was the 3-year recurrence of adenomas. Principal component analysis was used to identify dietary patterns from 50 food groups. Ninety-two patients presented new colorectal adenomas at the 3-year colonoscopy (65 men and 27 women). In men, three meaningful dietary patterns emerged from analysis, explaining 21.3% of variability. They were called 'Mediterranean', 'Sweets and snacks' and 'High fat and proteins' patterns. None of them were significantly related to the overall recurrence of colorectal adenomas either in univariate or multivariate analyses. Among women, the 'Mediterranean', the 'Western' and the 'Snacks' patterns explained 21.9% of variability. The 'Mediterranean' pattern characterized by a high consumption of olive oil, vegetables, fruit, fish and lean meat significantly reduced adenoma recurrence [second tertile: adjusted odds ratio (OR)=0.50, 95% confidence interval (CI)=0.18-1.42; third tertile: adjusted OR=0.30, 95% CI=0.09-0.98; P for linear trend=0.04]. The 'Western' and 'Snacks' patterns were not associated with recurrence among women. In conclusion, this study suggests that the Mediterranean dietary pattern may reduce the recurrence of colorectal adenomas, at least in women. These exploratory results need to be confirmed by larger studies.

Randomized study of biennial screening with a faecal occult blood test: results after nine screening rounds.

BACKGROUND: Two large true population studies in Europe have shown a significant reduction in mortality from colorectal cancer (CRC) by screening with a faecal occult blood test. In one trial conducted in Funen County, 61,933 individuals (aged 45-75 years) were randomly allocated either to a control group or to receive a biennial Hemoccult-II test. METHODS: These individuals were followed from 1985 to 2002 and 9 screening rounds were performed. RESULTS: First screening was accepted by 67% (20,672). Positivity rates varied between 0.8% and 3.8%, and the cumulative proportion of the test group having colonoscopy was 5.3%. Screen-detected CRC was early (Dukes' A) in 36% compared to 11% among controls. Incidence of CRC was unchanged, but mortality was reduced by 11%. This figure increased to 43% in persons participating in all 9 rounds. No more than 8,558 were screened at the 9th round. Patients with CRC detected between screenings had better survival than controls. Death rates from causes other than CRC among participants never became higher than among controls. CONCLUSION: The lesser reduction in mortality from CRC of 11% compared to 18% after 5 screening rounds may be explained by the decrease in the number screened. Efficacy in those screened supports the introduction of countrywide screening in Denmark, but it must be ascertained that acceptability, proportion of early CRC and logistics all reach the same standard as in the randomized trial.

Survival of rectal cancer patients in Denmark during 1994-99.

OBJECTIVE: As survival from rectal cancer in Denmark is below the European average, we analysed survival during the period of 1994-99 focusing upon improvement strategies. METHOD: All patients with a first-time rectal cancer were registered in a national database during this 5-year period. In the observational cohort study, data on patient age and gender, tumour stage, surgical procedures, adjuvant radiotherapy, anastomotic leakage, 30-day mortality and long-term survival were evaluated. RESULTS: The database comprised 5021 patients. Sixty-four percent had a localized tumour. Less than a third of patients with fixed tumours had pre-operative radiotherapy and curative surgery was achieved in 70%. Anastomotic leakage occurred in 13%, and 30-day mortality was 4% following abdominoperineal or anterior resection and 11% following a Hartmann's procedure. The relative 5-year survival in the entire series was 39% in males and 47% in females, respectively. Following curative surgery the relative 5-year survival was 55% in males and 63% in females, respectively. Survival was 71% in the subset of patients receiving curative total mesorectal excision. CONCLUSION: The average tumour stage upon diagnosis was probably more advanced compared to the other Nordic countries and pre-operative radiotherapy was administered to a minority of patients with fixed tumours. The anastomotic leakage rate was relatively high, whereas the 30-day mortality was comparable to other studies. Survival from rectal cancer in Denmark is still less favourable compared to the other Nordic and several European countries but improved from 1996 and onwards.

Colorectal adenoma characteristics as predictors of recurrence.

PURPOSE: The identification of groups with a high risk of colorectal adenoma recurrence remains a controversial issue for clinicians. This study was designed to assess the predictive value of initial patient and adenoma characteristics of the three-year recurrence. METHODS: The study population was composed of 552 patients with resected colorectal adenomas who completed the European Fiber-Calcium Intervention trial. At both baseline and three-year examinations, the characteristics of adenomas were recorded according to a standardized protocol. The main outcomes measured were the three-year overall recurrence, recurrence of multiple adenomas, recurrence of advanced adenomas (size > or = 1 cm or tubulovillous/villous architecture or moderate/severe dysplasia), and proximal and distal recurrence. RESULTS: A three-year recurrence was observed in 122 patients (22.1 percent), and more than one-half of them had recurrent adenomas on the proximal colon. After adjustment for patient characteristics and treatment allocation, the number of adenomas and their proximal location at baseline were the main predictors of recurrence. In comparison with patients who had one or two adenomas on the distal colon, patients with three or more adenomas with at least one of them located on the proximal colon had a much higher risk of overall recurrence (5.3; 95 percent confidence interval, 2.7-10.3), proximal recurrence (8.5; 95 percent confidence interval, 4.1-18), and advanced adenoma recurrence (5.5; 95 percent confidence interval, 2.4-12.6). CONCLUSIONS: Follow-up colonoscopies in patients with adenomas should include careful examination of the proximal colon. The time interval between follow-up examinations could probably be extended beyond three years in patients who have only one or two distal adenomas.

Colon polyps and cancer.

Screening for colorectal neoplasia still is the best method of reducing the mortality due to colorectal cancer, and it is to be hoped that fecal occult blood test programs will expand in the near future and be combined with appropriate endoscopy. There are substantial problems with compliance in large programs with occult blood tests as well as endoscopy. Colonography and DNA testing in feces are not yet suitable for population screening. Diagnostic strategies in symptomatic patients are becoming more selective, in the hope of avoiding many superfluous examinations without increasing the risk of missing cancers. New results have confirmed the preventive effect of long-term aspirin use on adenoma recurrence, but the most cost-effective dosage is not clear; the mechanism of action is also uncertain, but seems to involve cyclooxygenase-2. The risk of adenomas does not appear to be associated with low consumption of folate, but with low intake of fiber. A number of biomarkers have been evaluated in polyp patients, but so far surveillance is still based on endoscopic experience, which is less than optimal. Attempts have been made to restrict the number of surveillance endoscopies and reduce the pathologist's workload. The place of argon plasma coagulation has been clearly defined in connection with piecemeal removal of large sessile adenomas. Advances have been achieved in surgery and radiotherapy for rectal cancer, and acute surgery for colonic cancer with severe obstruction will be less common after the introduction of the metal stent.

Recurrence and survival after mesorectal excision for rectal cancer.

BACKGROUND: Mesorectal excision for rectal cancer has resulted in local recurrence rates of 3-11 per cent compared with up to 38 per cent after conventional methods. The results of a prospective Danish study with a historical control group are presented. METHODS: Three hundred and eleven patients with a mobile rectal cancer had mesorectal excision with curative intent performed by certified surgeons and were followed for 3 years. Demographic, perioperative and follow-up data were recorded prospectively. A series of patients who had conventional operations for rectal cancer served as a control group. RESULTS: The cumulative 3-year local recurrence rate was 11 per cent after mesorectal excision compared with 30 per cent after conventional surgery (hazard ratio (HR) 0.33 (95 per cent confidence interval (c.i.) 0.21 to 0.52); P < 0.001). Multivariate regression analysis showed that only advanced age (HR 0.97 (95 per cent c.i. 0.94 to 1.00); P = 0.048) and tumour in the lower third of the rectum (HR 0.21 (95 per cent c.i. 0.04 to 1.97); P = 0.075) were marginal independent predictors of local recurrence after mesorectal excision. The cumulative crude 3-year survival rate was 77 per cent after mesorectal excision and 62 per cent after conventional surgery (HR 0.58 (95 per cent c.i. 0.43 to 0.77); P < 0.001). Age was the only independent predictor of death after mesorectal excision (HR 1.04 (95 per cent c.i. 1.02 to 1.07); P = 0.001). CONCLUSION: Mesorectal excision is associated with a considerably lower risk of local recurrence and a better survival rate than conventional surgery, and is the optimum method for rectal cancer resection.

Diagnostic yield in a biennial Hemoccult-II screening program compared to a once-only screening with flexible sigmoidoscopy and Hemoccult-II.

BACKGROUND: Flexible sigmoidoscopy (FS) has a higher degree of sensitivity for detecting colorectal neoplasia in the left side of the colon than Hemoccult (H-II). However, no randomized controlled trial has compared a single FS screening with a H-II screening program (annual or biennial) despite the well-documented mortality reduction from colorectal cancer (CRC) in the latter. The aim was to compare the diagnostic yield of colorectal neoplasia in two aged-matched groups from two different randomized screening trials; one group screened by a single FS+H-II, the other with biennial H-II over the course of 16 years. METHODS: 24,465 persons invited to participate in the Funen biennial H-II screening program were compared with 4,460 similar persons invited to another Funen trial using a single FS+H-II. RESULTS: Compliance in the biennial H-II program was 65.5% during the first screening round compared to 39.8% for FS+H-II. The cumulative number of persons with positive tests was 8.2% (positive H-II) in the biennial H-II program during 16 years and 20.3% (polyps > 3 mm in diameter seen at FS or positive H-II) for once-only FS+H-II. The diagnostic yield of CRC per 1,000 screened was 9.9 in the biennial H-II program and 6.6 after FS+H-II (6.5 and 2.7 per 1,000 invited). The yield of advanced adenomas (> or = 10 mm and/or villous structure and/or severe dysplasia) was 2.3% in the H-II program and 3.3% after FS+H-II among the screened persons, but this difference disappeared when persons invited, but not necessarily screened, were compared (1.5% versus 1.3%). CONCLUSION: Screening with H-II in a biennial screening program during 16 years detected more CRCs than a single screening with FS+H-II and a similar number of advanced adenomas.

Upper gastrointestinal cancer in a population-based screening program with fecal occult blood test for colorectal cancer.

BACKGROUND: Screening with Hemoccult-II (H-II) followed by colonoscopy, when fecal occult blood is demonstrated, reduces mortality from colorectal cancer. Whether upper gastrointestinal investigation is necessary when colonoscopy does not reveal any significant colorectal lesion is doubtful, and is the subject of this study. MATERIAL: In 1985, 30,967 persons from the general population register of Funen were randomized to biennial H-II screening. A positive test was followed by colonoscopy and no attempt was made to evaluate the upper gastrointestinal tract. Based on the information from the Funen Patient Database, the National Board of Health's Register of Death Causes, the Cancer Register and the National Register of Patients, all persons with malignancy of the gastrointestinal tract were identified. RESULTS: During 15 years and 8 screening rounds, 1,767 tests were positive; 1,536 complete colonic investigations detected colorectal cancer in 182 persons, adenoma > or = 10 mm in 440 persons, and in 879 investigations no colorectal lesion was found. Upper GI cancers were diagnosed in 209 persons within 2 years of the H-II test (199 after a negative H-II and no more than 10 persons within 2 years of a positive test). Among the 10, two were diagnosed as a consequence of symptoms at the time of screening. CONCLUSION: It is unjustified to perform upper gastrointestinal investigation in asymptomatic persons with a positive H-II in a Danish population screening for colorectal cancer.

A randomised study of screening for colorectal cancer using faecal occult blood testing: results after 13 years and seven biennial screening rounds.

BACKGROUND: Three randomised trials have demonstrated reduction in mortality from colorectal cancer (CRC) by repeated screening with faecal occult blood tests, including the trial presented here, which is the only one still in progress. AIMS: To evaluate reduction in mortality after seven screening rounds and the possible influence of compliance on mortality from CRC. METHODS: At Funen in Denmark, random allocation to biennial screening with Hemoccult-II in 30 967 subjects aged 45-75 years and 30,966 controls was performed in 1985 from a population of 137,485 of the same age. Only participants who completed the first screening round were invited for further screening. Colonoscopy was offered if the test was positive. The primary end point was death from CRC, and the 10 year results were published in 1996. RESULTS: From the beginning of the first screening to the seventh round, mean age increased from 59.8 to 70.0 years in the screening and control groups, and the male/female ratio decreased from 0.92 to 0.81. Those who accepted screening were younger than non-responders. Positivity rates varied from 0.8% to 3.8%, the cumulative ratio of a positive test was 5.1% after seven rounds, and 4.8% of patients had at least one colonoscopy. Mortality from CRC was significantly less in the screening group (relative risk (RR) 0.82 (0.69-0.97)), and the reduction in mortality was most pronounced above the sigmoid colon. After seven rounds, RR was reduced to less than 0.70 compared with controls. Mortality rates from causes other than CRC did not differ. Non-responders had a significantly increased risk of death from CRC compared with those who accepted the full programme. Subjects who accepted the first screening, but not subsequent ones, demonstrated a tendency towards increased risk. CONCLUSIONS: The persistent reduction in mortality from CRC in a biennial screening program with Hemoccult-II, and a reduction in RR to less than 0.70 in those adhering to the programme, support attempts to introduce larger scale population screening programmes. The smaller effect on mortality from CRC in the rectum and sigmoid colon suggests evaluation by additional flexible sigmoidoscopy with longer intervals.

Colon polyps and cancer.

The superiority of colonoscopy to double-contrast barium enema in detecting neoplasia was finally demonstrated in 2000, but colonoscopic surveillance programs are still based on short-term observations and are mostly inadequate, despite the prospective design of the trials. The evaluation of the diagnostic accuracy of virtual colonoscopy is in progress, but its appropriate place in clinical gastroenterology has not yet been defined. There is now solid evidence that screening with fecal occult blood testing (FOBT) not only reduces the mortality from colorectal cancer, but also that the incidence is substantially reduced after removal of the precursor lesions. Feasibility studies for population screening are ongoing. A once-only sigmoidoscopy will probably not be an optimal method of screening, but may be added to a program with FOBT. Molecular stool screening is attractive, but still experimental. Colonoscopy is not attractive as an initial screening instrument, despite its high diagnostic accuracy, and should only be used for screening high-risk individuals. Genetic methods are playing an increasing role in defining prognostic markers for intestinal neoplasia, and it is recommended that information services should be established for the public. Chemopreventive studies have revealed that dietary fiber supplementation may not reduce the risk of adenomas; the opposite seems to be true for aspirin and non-aspirin NSAIDs, which are active in the early phase of carcinogenesis. New techniques for optimizing diagnostic and therapeutic colonoscopy have been introduced.

Collagen metabolites in the peripheral and splanchnic circulation of patients with Crohn disease.

BACKGROUND: Fragments of collagen arising during synthesis and breakdown have been suggested as markers of fibrous tissue remodelling in Crohn disease. We compared serum concentrations of the C-terminal propeptide of collagen I (PICP), the N-terminal propeptide of collagen III (PIIINP) and the C-terminal telopeptide of type I collagen (ICTP) in the splanchnic and systemic circulation in Crohn disease requiring segmental intestinal resection. METHOD: 15 consecutive patients undergoing surgery due to strictures or continuous inflammation. Male:female ratio was 6:9. Blood was drawn from a peripheral vein prior to surgery. Immediately before intestinal resection, additional samples were drawn from the antecubital vein and from a mesenteric vein draining the affected intestinal segment. PIIINP, PICP and ICTP were measured with radioimmunoassays. RESULTS: Pre-surgery S-ICTP (median 5.5 microg/L; range 3.2-17.2 microg/L) was significantly increased in peripheral blood compared with healthy controls (median 2.6 microg/L; range 0.6-5.7 microg/L), P < or = 0.05. By contrast, S-PICP (median 98 microg/L; range 62-137 microg/L) and S-PIIINP (median 2.5 microg/L; range 1.2-7.4 microg/L) were significantly lower than S-PICP (median 133 microg/L; range 66-284 microg/L) and S-PIIINP (median 3.4 microg/L; range 1.0-7.1 microg/L) in healthy controls, P < or = 0.05. During surgery. no difference in S-PICP and S-PIIINP was documented between peripheral blood and splanchnic blood. In contrast, S-ICTP was increased in splanchnic blood (median 6.2 microg/L; range 2.7-17.4) compared to peripheral blood (median 5.0 microg/L; range 3.1-13.4) (P=0.05). CONCLUSION: The present study provides further evidence that the altered intestinal collagen metabolism in Crohn disease is reflected in the local and systemic circulation.

[Recurrence and survival after conventional low anterior resection for rectal cancer]. / Recidiv og overlevelse efter konventionel lav anterior resektion for cancer recti.

INTRODUCTION: The aim of the study was to evaluate the incidence of recurrence of local cancer, distant metastases and survival after conventional low anterior resection for cure in patients with rectal carcinoma, on the basis of the poor prognosis after colorectal cancer in Denmark. MATERIAL AND METHODS: Consecutive patients operated on in the nine Danish departments of surgical gastroenterology in 1992-1993. Retrospective collection of data on recurrence of local cancer, distant metastases, and over-all survival at the end of 1996. RESULTS: Of 268 patients, 77 (29%) developed recurrent local cancer and/or distant metastases. Forty-eight (18%) had local recurrence with a cumulative 5-year rate of 39%. Distant metastases were seen in 54 (20%). The local recurrence rate increased with increasing Dukes' tumour stage and was higher after operation by a non-specialist (30%) than by a consultant, another specialist, or a surgeon under training and supervised by a consultant (15-17%) (p = 0.04). Multiple regression showed that the recurrence rate was independent of tumour localisation, blood loss, transfusion, anastomotic leakage, and status of the surgeon. The cumulative crude 5-year survival was 50% and independent of the status of the surgeon. DISCUSSION: Our relatively high local recurrence rate and the results in the literature after total mesorectal excision (TME) indicate that the conventional technique should be replaced by TME, which has become the recommended method in recent years. Furthermore, we propose a changed strategy in the treatment of rectal cancer. The patients should be treated in fewer departments with established teams of rectal cancer specialists taking part in all operations for rectal cancer.

Assessments of clonal composition of colorectal adenomas by FISH analysis of chromosomes 1, 7, 13 and 20.

Chromosome banding analysis has shown that numerical aberrations, in particular gains of chromosomes 7, 13 and 20, are common in colorectal adenomas but cannot provide reliable information on the size of the abnormal clones in vivo. We examined interphase nuclei from 70 colorectal adenomas, of which 64 had been previously karyotyped, using fluorescence in situ hybridization (FISH) with probes for the pericentromeric regions of chromosomes 1, 7, 13 and 20. Gain of chromosome 7 was seen in 34% of the analyzed adenomas, +13 was seen in 44% and trisomy 20 was found in 32% of the adenomas, verifying that the trisomies are in vivo phenomena. The median proportion of cells with trisomy was larger than 50%. A comparison with the G-banding analysis showed a good correlation between the results yielded by the 2 methods. Based on the clonal size and karyotypic findings, a likely order of events during clonal evolution could be ascribed to each case. More than 1 numerical aberration was detected by FISH analysis in 16 adenomas. In 6 adenomas, a clone with only trisomy 7 was present alongside a clone with additional gain(s) of chromosomes 13 and/or 20. Seven cases had gain of chromosome 13 and/or gain of chromosome 20 in the largest clone, suggesting that a clone with either of these changes was present before the changes in chromosome 7 copy number took place. On the basis of the results of this combined meta- and interphase cytogenetic study, we conclude that gains of chromosomes 7, 13 and 20 are common in colorectal adenomas and that the trisomies usually are present in a large proportion of the cells. They seem to be primary chromosome aberrations in some adenomas, whereas in others they arise secondarily as part of the clonal evolution. Although the first gain usually is of chromosome 7, it is evident that it is the end result of the chromosomal aberrations, not the exact sequence in which they occur, that determines the pathogenetic consequences.

Colonic screening and surveillance.

Screening for colorectal cancer has not obtained worldwide acceptance in spite of its proven survival benefit for average-risk persons and some high-risk groups. The incidence of and mortality from colorectal cancer are worrying in Europe as well as in the USA, Australia and Japan. The best evidence-based studies are those published on screening using faecal occult blood tests, endoscopic methods and different tumour markers having been evaluated to a lesser degree. Feasibility studies are necessary before massive screening can be undertaken because the results obtained from randomized studies may not be reproduced to a satisfactory degree in average- as well as high-risk populations. Primary prevention by dietary intervention and drugs has been studied in great detail, so far without any major breakthrough. This chapter will address different screening methods in populations with a varying risk of colorectal cancer, together with providing a short review of prevention and intervention strategies.

A new fecal calprotectin test for colorectal neoplasia. Clinical results and comparison with previous method.

BACKGROUND: Fecal calprotectin is elevated in patients with colorectal cancer (CRC). An improved method has been developed. The aim was to evaluate sensitivity and specificity for CRC with the new fecal calprotectin method and to compare the results with those of the original method. METHODS: The study comprised 453 subjects including symptomatic CRC patients and CRC high risk subjects with and without CRC. Complete colonoscopy was performed. Calprotectin was measured with an enzyme linked immunosorbent assay (ELISA) using small (50-100 mg) feces samples. RESULTS: Fecal calprotectin levels were significantly elevated in symptomatic CRC and in asymptomatic CRC detected in high risk subjects. Calprotectin levels were significantly decreased 3 months after cancer removal. A cut-off limit of 50 microg/g resulted in a sensitivity of 89% in CRC patients and 79% in high risk subjects, compared to 89% and 75%, respectively, with the original method, using 10 mg/l as cut-off limit. Specificity was improved with the new method to 68% and 91% at cut-off of 50 and 150 microg/g, compared to 66% and 88%, respectively. Negative predictive value (NPV) was 99% for cut-off of 50 microg/g in the high risk population. One stool sample was sufficient, but measurement of two spots in two stools increased sensitivity to 98% for symptomatic and 82% for asymptomatic CRC. CONCLUSION: The new simple method, using small samples of feces, had a higher diagnostic accuracy, suggesting that it should be preferred to the original one, in screening high risk groups for CRC.