Claus Fenger

Randomised study of screening for colorectal cancer with faecal-occult-blood test

BACKGROUND Case-control studies and a voluntary-based follow-up study have suggested that repeated screening with faecal-occult-blood (FOB) tests can lead to a reduction in mortality from colorectal cancer (CRC). The aim of this randomised study was to compare mortality rates after FOB tests every 2 years during a 10-year period with those of unscreened similar controls. METHODS 140,000 people aged 45-75 years lived in Funen, Denmark, in August, 1985, and were considered for inclusion in our study. Before randomisation we excluded individuals who had CRC or precursor adenomas and those who had taken part in a previous pilot study. Randomisation of 137,485 people in blocks of 14 allocated three per 14 to the screening group (30,967), three per 14 to the control group (30,966), and eight not to be enrolled in the study (75,552). Controls were not told about the study and continued to use health-care facilities as normal. Hemoccult-II blood tests (with dietary restrictions but without rehydration) were sent to screening-group participants. Only those participants who completed the first screening round were invited for further screening--five rounds of screening during a 10-year period. Participants with positive tests were asked to attend to full examination and were offered colonoscopy whenever possible. The primary endpoint was death from CRC. FINDINGS Of the 30,967 screening-group participants, 20,672 (67%) completed the first screening round and were invited for further screening; more than 90% accepted repeated screenings. During the 10-year study, 481 people in the screening group had a diagnosis of CRC, compared with 483 unscreened controls. There were 205 deaths attributable to CRC in the screening group, compared with 249 deaths in controls. CRC mortality, including deaths attributable to complications from CRC treatment, was significantly lower in the screening group than in controls (mortality ratio 0.82 [95% CI 0.68-0.99]) p = 0.03). INTERPRETATION Our findings indicate that biennial screening by FOB tests can reduce CRC mortality. This study is being continued to improve its statistical power and to assess the effect of the removal of more precursor adenomas in the screening-group participants than in controls on CRC incidence.

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.

Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells

The purpose of this study was to clarify whether HLA-DR expression of colorectal tumour cells or the CD4+/CD8+ ratio of the tumour infiltrating lymphocytes is significantly associated with the prognosis of colorectal cancer. Using flow cytometry, we studied the tumour cell expression of the HLA class II in 70 enzymatically dissociated colorectal cancers and the phenotype of tumour infiltrating lymphocytes (TILs) in 41 cases. There was no trend in 5-year survival between three levels (low, medium, high) of HLA-DR expression on the tumour cells. Patients with low CD4+/CD8+ ratios had a better clinical course, with significantly higher 5-year survival, p=0.046, independent of the Dukes stage and age. Our results have implications for tumour immunology; colorectal cancer cells might be a target for cytotoxic T-lymphocytes, however the tumour cells are not able to initiate an immune response. Stimulation of the immune system could possible be obtained using dendritic cells cultured in vitro and loaded with tumour antigens.

The Funen Adenoma Follow-up Study: Incidence and Death from Colorectal Carcinoma in an Adenoma Surveillance Program

The results of a prospective randomized study of 1056 patients with colorectal adenomas are presented. After initial polypectomy from 1978 to 1992, patients were allocated at random to different follow-up intervals varying from 6 to 48 months, except 53 patients who were allocated to intervals of 6 months. The examinations were mainly done by colonoscopy. Ten patients developed colorectal carcinoma, a number similar to that expected (7.96), when compared with a sex- and age-matched normal Danish population. The expected number of carcinomas was also calculated from adenoma to carcinoma conversion rates estimated in other studies and compared with that observed. If all carcinomas develop in large (> or = 10 mm) adenomas or adenomas with severe dysplasia, the expected number of carcinomas would have been 62 and 110, respectively, indicating a significant reduction of carcinomas in the present study. One patient died of colorectal carcinoma, which is significantly lower than the number expected (7.58). Two patients died of complications from therapeutic and diagnostic colonoscopy--that is, 2 deaths in 3959 colonoscopies. In conclusion, the follow-up strategy has resulted in a mortality from colorectal carcinoma which is reduced when compared with the normal population, in spite of an apparently similar incidence of carcinoma. However, previous suggested adenoma-carcinoma conversion rates indicate that a major reduction of incidence actually has taken place.

Clinical Benefit of a Gluten-Free Diet in Type 1 Diabetic Children With Screening-Detected Celiac Disease: A population-based screening study with 2 years’ follow-up

OBJECTIVE—This study was performed to 1) determine the prevalence of celiac disease in Danish children with type 1 diabetes and 2) estimate the clinical effects of a gluten-free diet (GFD) in patients with diabetes and celiac disease. RESEARCH DESIGN AND METHODS—In a region comprising 24% of the Danish population, all patients <16 years old with type 1 diabetes were identified and 269 (89%) were included in the study. The diagnosis of celiac disease was suspected in patients with endomysium and tissue transglutaminase antibodies in serum and confirmed by intestinal biopsy. Patients with celiac disease were followed for 2 years while consuming a GFD. RESULTS—In 28 of 33 patients with celiac antibodies, an intestinal biopsy showed villous atrophy. In 5 patients, celiac disease had been diagnosed previously, giving an overall prevalence of 12.3% (95% CI 8.6–16.9). Patients with celiac disease had a lower SD score (SDS) for height (P < 0.001) and weight (P = 0.002) than patients without celiac disease and were significantly younger at diabetes onset (P = 0.041). A GFD was obtained in 31 of 33 patients. After 2 years of follow-up, there was an increase in weight SDS (P = 0.006) and in children <14 years old an increase in height SDS (P = 0.036). An increase in hemoglobin (P = 0.002) and serum ferritin (P = 0.020) was found, whereas HbA1c remained unchanged (P = 0.311) during follow-up. CONCLUSIONS—This population-based study showed the highest reported prevalence of celiac disease in type 1 diabetes in Europe. Patients with celiac disease showed clinical improvements with a GFD. We recommend screening for celiac disease in all children with type 1 diabetes.

Repeated Screening for Colorectal Cancer with Fecal Occult Blood Test: A Prospective Randomized Study at Funen, Denmark

Two screenings with Hemoccult-II were performed in a randomized study, allocating 30,970 persons to screening and 30,968 as controls in a population of 140,000 between 45 and 74 years old on the island of Funen, Denmark. The test was completed in 20,672 initially and in 18,779 of these during rescreening 2 years later. Positive H-II tests were found in 215 and 159 persons during the two screenings, respectively. A total colonoscopy was performed in 187 and 144, and cancer was detected in 37 and 13 and adenomata in 86 and 76, respectively. Interval cancers had developed in 40 persons at the end of the second screening, and 39 non-responders had developed cancer. Cancer was diagnosed in 115 controls and an adenoma in 100 during the same period. Interval cancers presented as rectal cancers more frequently than those detected by screening. Early cancers were more frequent in the screening group, and, accordingly, more patients had curative and also less extensive surgery, with a low postoperative mortality. The total number of deaths from colorectal cancer was 37 in the screening group, including interval cancers and cancers in non-responders and persons who developed cancer before they could be invited, which suggests a reduction in mortality of 27% (51 deaths among controls, compared with 37). The reduction is as yet not statistically significant, and final evaluation must await at least one more screening, ending in 1990, and a follow-up of some years. Removal of more large adenomas during screening makes it possible that the incidence of cancer will decrease.

Initial Mass Screening for Colorectal Cancer with Fecal Occult Blood Test: A Prospective Randomized Study at Funen in Denmark

A Danish study allocated at random 30,970 persons to screening with Hemoccult-II and 30,968 as controls in a population of 140,000 between 45 and 74 years old. Persons with known colorectal cancer, adenoma, and distant spread from all types of cancer were excluded. The test was completed in 20,672 persons from August 1985 to September 1986, and 215 (1%) were found to be positive. Colonoscopy in 203 and double-contrast barium enema in 6 detected 37 persons with cancer and 86 with adenomas. Dukes A cancer was detected in 19 in the screening group, in contrast to 2 among controls. Synchronous adenomas were found in 23 with a positive test and 10 controls. Interval cancer was found in nine persons within 1-11 months after a negative test. Eighteen persons got cancer before invitation and six defectors as well. In all, colorectal cancer was detected in 70 persons in the screening group and in 38 controls; the figures for adenomas alone were 103 and 38, respectively. The study is designed to detect a possible reduction in mortality from colorectal cancer of 25% within 5 years after three screenings with intervals of 2 years. The second screening will begin in September 1987. It remains to be shown whether a reduction may be obtained both in mortality and in incidence of colorectal cancer.

Colorectal Adenoma Characteristics as Predictors of Recurrence

PURPOSEThe 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.METHODSThe 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 ≥ 1 cm or tubulovillous/villous architecture or moderate/severe dysplasia), and proximal and distal recurrence.RESULTSA 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).CONCLUSIONSFollow-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.

Recurrence and survival after mesorectal excision for rectal cancer

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.

Possible Advantages and Drawbacks of Adding Flexible Sigmoidoscopy to Hemoccult-II in Screening for Colorectal Cancer: A Randomized Study

BACKGROUND Flexible sigmoidoscopy (FS) has been recommended as a screening method to reduce mortality from colorectal cancer (CRC). The present study evaluates the effect of adding FS to the fecal occult blood test Hemoccult-II (H-II) on diagnostic yield of colorectal neoplasia. METHODS A total of 10,978 normal persons aged 50-75 years were invited to participate, 5495 persons being allocated at random to H-II and FS and 5483 to H-II alone. RESULTS In spite of a lower compliance (40% versus 56%) for the combined procedure, the diagnostic yield of colorectal neoplasia was higher than for H-II alone (12 CRC versus 4 CRC, and 72 large adenomas versus 14). Within 24-62 months after screening there were fewer CRCs detected after H-II + FS than after H-II alone. The stage distribution was less favorable than in screen-detected cases. CONCLUSION One FS may not be an optimal way of screening, but FS deserves to be evaluated in randomized population studies including repeated H-II tests in the control arm.