Earlier diagnosis and treatment of symptomatic bowel cancer: can it be achieved and how much will it improve survival?

AIM: To determine current delays in diagnosis and treatment of bowel cancer, when and why they occur, and what effect they have on survival. METHOD: A detailed review of the literature based on the development of the GP referral guidelines in 2000. RESULTS: There is no evidence of a reduction in the delay to diagnosis and treatment of bowel cancer over the last 60 years. There is no strong theoretical basis for a benefit from earlier diagnosis of symptomatic bowel cancer and this is consistent with observational studies. CONCLUSION: Campaigns to earlier diagnose bowel cancer will not be successful unless new strategies are developed. There is substantial evidence that earlier diagnosis of symptomatic bowel cancer will not improve survival in the majority of patients. However as excessive delays still occur in some patients it is reasonable to continue to aim to diagnose and treat all bowel cancer within 6 months of the onset of symptoms with an overall median of 3-4 months.

Downstaging of colorectal cancer by the National Bowel Cancer Screening programme in England: first round data from the first centre.

OBJECTIVE: Data from randomized controlled trials of Colorectal Cancer (CRC) screening in Nottingham, UK and Funen, Denmark and pilot data from the English and Scottish arms of the National Bowel Cancer Screening Programme (NBCSP) have demonstrated predominantly early-stage disease amongst the screened population. The aim of this study was to investigate whether downstaging of cancers occurred in the NBCSP in Wolverhampton. METHOD: A case-control study was performed to compare the staging of CRC diagnosed in the NBCSP-screened population during the prevalent round (2 years) of screening, with cancers diagnosed prior to the introduction of the NBCSP. RESULTS: The total population in the screening area is 899 000. A total of 108 346 FOB kits were sent out of which 55 931 were returned (51.6% uptake), A total of 1039 colonoscopies were performed with a 94.75% unadjusted caecal intubation rate. There were three complications (haemorrhages 3) and no perforations. The NBCSP in Wolverhampton identified 106 (75% male) CRC in the first 2 years with 45.3% Dukes A, 21.7% B, 29.2% C and 3.8% D. Two hundred and fifty-six (61% male) CRC were identified in the control group, 10.1% Dukes A, 50.0% B, 36.3% C and 3.5% D. There was a highly significant shift towards earlier stage disease in the screened group (P < 0.0001). CONCLUSION: The 2-year data from the first English centre to start bowel cancer screening demonstrates significant downstaging of cancer, consistent with both the RCT and pilot data.

Patient-led variable dosing with balsalazide as long-term therapy for maintenance in ulcerative colitis: a 3-year prospective observational study.

BACKGROUND: The patient-centred approach is new to the management of ulcerative colitis. To date, it has only been shown to be successful in a short-term study. AIM: To assess the feasibility, safety and efficacy of patient-led dosing using balsalazide in the long-term treatment of ulcerative colitis. METHODS: This was a 3-year, two-cohort, multi-centre study: one cohort was in stable remission (52 patients) and the other was newly in remission (76 patients) from ulcerative colitis. Two 750-mg balsalazide capsules were given twice daily for maintenance, increased by 750-mg increments to a maximum of 6 g for up to 7 days depending on symptom severity. Clinical assessments were made every 12-14 weeks; laboratory assessments were made every 6 months. RESULTS: The average median daily dose of balsalazide was 3 g (range, 1.5-6 g). In the cohort with stable remission, 23 patients (44%) had relapsed by 3 years [median time to relapse, > 1095 days (36 months)]. In the cohort newly in remission, these values were 45 patients (59%) and 656 days (22 months), respectively. In the cohort with stable remission, the time since last relapse was significantly associated with relapse during the first year of treatment (P < 0.033). CONCLUSIONS: Long-term, patient-led, maintenance treatment with balsalazide is well tolerated with a good safety profile and is effective for patients with ulcerative colitis.

A prospective study of colonoscopy practice in the UK today: are we adequately prepared for national colorectal cancer screening tomorrow?

AIM: To study the availability and quality of adult and paediatric colonoscopy in three National Health Service (NHS) regions. METHOD: A prospective four month study of colonoscopies in North East Thames, West Midlands, and East Anglia. PATIENTS: Subjects undergoing colonoscopy in 68 endoscopy units. RESULTS: A total of 9223 colonoscopies were studied. The mean number of colonoscopies performed over the four month period was 142 in district general hospitals and 213 in teaching hospitals. Intravenous sedation was administered in 94.6% of procedures, but 2.2% and 11.4% of "at risk" patients did not have continuous venous access or did not receive supplemental oxygen, respectively. Caecal intubation was recorded in 76.9% of procedures but the adjusted caecal intubation rate was only 56.9%. Reasons for failing to reach the caecum included patient discomfort (34.7%), looping (29.7%), and poor bowel preparation (19.6%). A normal colonoscopy was reported in 42.1%. The most common diagnosis was polyps (22.5%) followed by diverticular disease (14.9%). Inflammatory bowel disease was recorded in 13.9% and carcinoma in 3.8%. Only half of the patients remembered being told of possible adverse events prior to the procedure. Rectal bleeding requiring admission following colonoscopy was reported in six patients. The overall perforation rate was 1:769 and colonoscopy was considered a possible factor in six deaths occurring within 30 days of the procedure. Only 17.0% of colonoscopists had received supervised training for their first 100 colonoscopies and only 39.3% had attended a training course. CONCLUSION: There is serious under provision of colonoscopy service in most NHS hospitals. Endoscopy sedation guidelines are not always adhered to and there is a wide variation in practice between units. Colonoscopy is often incomplete and does not achieve the target 90% caecal intubation rate. Serious complications of colonoscopy were comparable with previous studies. Training in colonoscopy is often inadequate and improved practice should result from better training.

Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome.

Germline mutations in the LKB1/STK11 tumour suppressor gene cause Peutz-Jeghers syndrome (PJS), a rare dominant disorder. In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions, PJS is associated with an increased risk of tumours at multiple sites. Follow-up information on carriers is limited and genetic heterogeneity makes counselling and management in PJS difficult. Here we report the analysis of the LKB1/STK11 locus in a series of 33 PJS families, and estimation of cancer risks in carriers and noncarriers. Germline mutations of LKB1/STK11 were identified in 52% of cases. This observation reinforces the hypothesis of a second PJS locus. In carriers of LKB1/STK11 mutations, the risk of cancer was markedly elevated. The risk of developing any cancer in carriers by age 65 years was 47% (95% CI: 27-73%) with elevated risks of both gastrointestinal and breast cancer. PJS with germline mutations in LKB1/STK11 are at a very high relative and absolute risk of multiple gastrointestinal and nongastrointestinal cancers. To obtain precise estimates of risk associated with PJS requires further studies of genotype-phenotype especially with respect to LKB1/STK11 negative cases, as this group is likely to be heterogeneous.

Low mortality in ulcerative colitis and Crohn's disease in three regional centers in England.

OBJECTIVES: Recent epidemiological studies suggest that mortality rates for inflammatory bowel disease (IBD) are similar to those of the general population. However, most of this work has been done in referred populations or larger urban centers. We intended to estimate mortality rates for ulcerative colitis (UC) and Crohn's disease (CD) in three British district general hospital practices in Wolverhampton, Salisbury, and Swindon. METHODS: Consecutive patients with CD or UC were identified from 1978 to 1986 and followed prospectively. Demographic data, date and cause of death or health status at December 31, 1993 were used to estimate standardized mortality ratios (SMRs) and 95% confidence intervals. RESULTS: Sixty-four deaths occurred in 552 patients (UC 41 of 356; CD 23 of 196). The overall SMRs were 103 [95% confidence interval (CI): 79-140] for UC and 94 (95% CI: 59-140) for CD. The respective SMRs were higher only in the first year after diagnosis at 223 (95% CI: 99-439; p = 0.02) and 229 (74-535; p = 0.056), and even then, most subjects died from non-IBD causes (5 of 13). Nonsurvivors were significantly older than survivors in both UC and CD (p < 0.01). The SMR was also significantly greater during a severe first attack of UC at 310 (95% CI: 84-793; p = 0.04). Patients with perianal or colonic CD had an increased SMR [396 (95% CI: 108-335; p = 0.02) and 164 (95% CI: 82-335; p = 0.02)] respectively, partly related to the older mean age (52 vs 32 yr, p < 0.001). CONCLUSIONS: Mortality rates are not increased in IBD compared with the general population. However, older patients may be at increased risk of dying from other causes early in the disease clinical course.

A critical review of epidemiological studies in inflammatory bowel disease.

This review addresses the difficulty in interpreting the results of epidemiological studies in IBD and in making meaningful comparisons between studies. Both ulcerative colitis and Crohn disease appear to be more common in some industrialized countries such as Scandinavia, United Kingdom, North America and less common in Central and Southern Europe, Asia and Africa. Given data showing an increased incidence of ulcerative colitis in the United Kingdom, it is crucial that more studies be conducted in developing countries. While the incidence of Crohn disease has increased strikingly in many areas, the incidence of ulcerative colitis has remained fairly stable in most. This could be due to the rising number of community-based studies, as well as the improved accuracy in diagnosing Crohn disease. Although, the incidence of IBD among Blacks in Africa is low, infection rates are high, life expectancy is lower than in developed countries. Data from the USA suggest that rates are similar in Afro-American and Caucasian populations. Rates for Jewish populations may be slightly higher than in non-Jewish populations but this also varies geographically. Careful attention to genetic, environmental, and socioeconomic factors must be accounted for in these studies. There is no strong evidence to support that IBD is more common in urban than in rural settings and migration towards more accessible health care has not been adequately addressed. Recent epidemiological studies suggest that mortality rates for IBD are similar to that of the general population for the majority of patients. However, older patients with IBD and newly diagnosed cases with severe diseases are at increased risk of dying. Epidemiological studies remain important in assisting with health policy planning and in hypothesis testing of etiological factors. As better diagnostic techniques become widely available and public health registries are increasingly used, it is possible that geographic differences will diminish. International collaborative studies will be better equipped to answer research questions addressing risk factors and disease natural history. We have summarized in Table V the essential criteria to conduct a sound epidemiological study, which would permit future testing of hypotheses among different populations.

Maintenance of remission of ulcerative colitis: a comparison between balsalazide 3 g daily and mesalazine 1.2 g daily over 12 months. ABACUS Investigator group.

BACKGROUND: Despite widespread use of aminosalicylates as maintenance treatment for ulcerative colitis (UC), patients still report troublesome symptoms, often nocturnally. AIM: To compare the efficacy and safety of balsalazide (Colazide) with mesalazine (Asacol) in maintaining UC remission. METHODS: A randomized, double-blind comparison of balsalazide 3 g daily (1.04 g 5-ASA) and mesalazine 1.2 g daily for 12 months, in 99 (95 evaluable) patients in UC remission. RESULTS: Balsalazide patients experienced more asymptomatic nights (90% vs. 77%, P=0.0011) and days (58% vs. 50%, N.S.) during the first 3 months. Balsalazide patients experienced more symptom-free nights per week (6.4+/-1.7 vs. 4.7+/-2.8; P=0.0006) and fewer nights per week with blood on their stools or on the toilet paper, mucus with their stools or with sleep disturbance resulting from symptoms or lavatory visits (each P < 0.05). Fewer balsalazide patients relapsed within 3 months (10% vs. 28%; P=0.0354). Remission at 12 months was 58%, in both groups. Similar proportions of patients reported adverse events (61% balsalazide vs. 65% mesalazine). There were five serious adverse events (two balsalazide, three mesalazine) and four withdrawals due to unacceptable adverse events (three balsalazide, one mesalazine), of which one in each group was also a serious adverse event. CONCLUSIONS: Balsalazide 3 g/day and mesalazine 1.2 g/ day effectively maintain UC remission and are equally well tolerated over 12 months. At this dose balsalazide prevents more relapses during the first 3 months of treatment and controls nocturnal symptoms more effectively.

Antibiotic prophylaxis in gastrointestinal endoscopy: a report by a Working Party for the British Society of Gastroenterology Endoscopy Committee.

Antibiotic prophylaxis is recommended for endoscopic procedures if the patient is at high risk of endocarditis or of symptomatic bacteraemia as a consequence of immunosuppression or neutropenia. In most circumstances parenteral amoxycillin and gentamicin are recommended. The addition of parenteral metronidazole is recommended in patients with neutropenia. Vancomycin or teicoplanin are recommended in patients allergic to penicillin. Antibiotic prophylaxis is recommended for all patients undergoing ERCP with evidence of biliary stasis or pancreatic pseudocyst. Oral ciprofloxacin or parenteral gentamicin (or parenteral quinolone, cephalosporin or ureidopenicillin) are recommended for ERCP.

Prevention of recurrence of oesophageal stricture, a comparison of lansoprazole and high-dose ranitidine.

OBJECTIVE: To determine the efficacy of lansoprazole 30 mg given in the morning compared with high-dose ranitidine 300 mg twice daily in the treatment of patients with oesophageal strictures. DESIGN: A multicentre, outpatient, double-blind, parallel group, prospectively randomized clinical trial. PATIENTS: One hundred and fifty-eight patients (lansoprazole 30 mg n = 78, ranitidine 600 mg n = 80) were enrolled from 19 centres in the UK over 23 months. INTERVENTIONS: Patients with an oesophageal stricture were randomized to receive either lansoprazole 30 mg once daily or high-dose ranitidine 300 mg twice daily for 12 months. Dilatation was performed at entry and repeat endoscopies were scheduled at 6 and 12 months and additionally at other times if there was symptomatic relapse. Redilatation was performed as required and according to a predefined scale. The patient's assessment of dysphagia over the previous 7 days was recorded by the investigator at 1, 3, 6, 9 and 12 months. Safety was assessed by laboratory tests, physical examination and all adverse events. MAIN OUTCOME MEASURES: Efficacy was assessed primarily by the time to redilatation, the proportion of patients requiring at least one redilatation, and the number of redilatations over 12 months. The relief of dysphagia and reduction in stricture grade were secondary efficacy measures. RESULTS: The time to redilatation was longer and the probability of no redilatation were higher in the lansoprazole group than in the ranitidine group; for all patients randomized (intention to treat principle), this difference was of borderline significance (life table, P = 0.053). The proportions of patients requiring at least one redilatation during the 12-month treatment period were 30.8% (24/78) with lansoprazole and 43.8% (35/80) with ranitidine (all patients randomized, chi 2 test, P = 0.092). Compared to ranitidine, patients receiving lansoprazole reported significantly lower dysphagia grades at 6 months (stratified Wilcoxon test, P = 0.0086) but not at 12 months (stratified Wilcoxon test, P = 0.074). A greater proportion of patients in the ranitidine group-33.8% (27/80)-withdrew prematurely compared to the lansoprazole group (26.9%, 21/78). The most frequent reasons for premature withdrawal were adverse events and protocol violations. There were no clinically significant differences in incidence or severity of adverse events between the two groups. The mean increase in gastrin levels after 12 months' treatment was significantly greater for patients in the lansoprazole group (124.2 pg/ml, P = 0.0056) than those in the ranitidine group (31.9 pg/ml). No significant changes in gastric mucosal histology were detected for patients in either group. CONCLUSION: It is concluded that lansoprazole 30 mg once daily is superior to ranitidine 300 mg twice daily in relieving dysphagia, and at least as effective in reducing the need for a repeat dilatation.

Sulphasalazine treatment and the colorectal mucosa-associated flora in ulcerative colitis.

AIM: To study the influence of sulphasalazine treatment on the mucosa-associated bacterial flora of rectal biopsy tissue specimens in patients with ulcerative colitis. PATIENTS: Twenty-four patients had newly diagnosed active ulcerative colitis; 20 patients had acute relapse of ulcerative colitis (10 not taking maintenance sulphasalazine); (40 patients had quiescent ulcerative colitis; 21 not taking maintenance sulphasalazine). The influence of 3 weeks of sulphasalazine treatment on the mucosa-associated flora was studied in the patients presenting with active disease. RESULTS: Comparison of patients according to sulphasalazine usage revealed few differences in the mucosal flora. In patients with quiescent ulcerative colitis, Escherichia coli was found at lower counts in patients taking maintenance sulphasalazine; however, this effect was not evident in patients with active disease. Inconsistent changes in other facultatives were seen between the two active disease groups, particularly for a miscellaneous group of unidentified Gram-positive rods. Three patients, all receiving sulphasalazine, were colonized with Clostridium difficile, but this did not appear to influence their disease. CONCLUSION: Sulphasalazine treatment in ulcerative colitis causes only minor disturbance to the populations of bacteria colonizing the colorectal mucosa.

Inflammatory bowel disease and domestic hygiene in infancy.

To test the hypothesis that Crohn's disease is caused by delayed exposure to enteric infections, we did a case-control study. We compared 133 patients who have Crohn's disease and 231 with ulcerative colitis who have controls selected from the general population and matched for age and sex. Crohn's disease was more common in subjects whose first houses had a hot-water tap (odds ratio 5.0, 95% CI 1.4-17.3) and separate bathroom (3.3, 1.3-8.3). Ulcerative colitis showed no clear relation to household amenities in infancy. These findings may explain why the incidence of Crohn's disease has increased in developed countries over the past 50 years.

Phenotypic and genotypic variation in Giardia lamblia isolates during chronic infection.

Two Giardia isolates were axenised in vitro after recovery by duodenal aspiration from a man with hypo-gamma globulinaemia and chronic giardiasis, before and after three unsuccessful courses of metronidazole. In vitro drug sensitivity assays showed that the pretreatment isolate was sensitive to metronidazole with minimum inhibitory concentration (MIC) and dose that inhibited growth by 50% (ED50) values of 0.1 and 0.03 mumol/l, respectively. The post-treatment isolate was 20-fold more resistant (MIC and ED50 4.3 and 0.58 mumol/l, respectively). Differences between these isolates were also found in the surface protein profiles after radioiodination, metabolic labelling patterns with 35S-methionine, malic enzyme isoenzyme patterns, and by DNA fingerprinting with a M-13 bacteriophage probe. The phenotypic and genotypic differences between the pretreatment and post-treatment isolates suggest that we have isolated two different strains from the same patient and that treatment with metronidazole resulted in selection of the more resistant strain.

Adhesive and hydrophobic properties of Escherichia coli from the rectal mucosa of patients with ulcerative colitis.

The adherent properties and hydrophobicity of Escherichia coli isolates have been compared from the rectal mucosa of patients with active and inactive ulcerative colitis and from a control patient group. Patients with active colitis were colonised less frequently and with lower numbers of E coli than were control patients. Mannose resistant adhesion to HEp-2 cells was determined for 124 isolates of E coli and surface hydrophobicity was estimated by salt agglutination in 96 of these isolates. There was no significant difference in the distribution of adherent strains between the colitis patient groups or with disease activity. E coli from the control patients were marginally less adhesive than those from colitics. The hydrophobicity of isolates did not differ significantly between colitic and control groups nor were there significant differences correlated with disease activity. Furthermore, for these mucosal E coli isolates, hydrophobicity and mannose resistant adhesion were unrelated characteristics.

Short report: comparison of two doses of balsalazide in maintaining ulcerative colitis in remission over 12 months.

In a four-centre prospective double-blind trial, 108 patients with ulcerative colitis in remission were randomized to receive balsalazide in doses of 3 g or 6 g/day for 12 months. The patients were assessed at 3-monthly intervals clinically, sigmoidoscopically and with routine haematology and biochemistry. Remission rates of 77% (3 g/day) and 68% (6 g/day) at 12 months were not significantly different. Intolerance reactions leading to withdrawal from the study occurred in only 9 patients (8%), all occurring in the first 7 weeks of the study. Balsalazide is therefore both highly effective in maintaining remission in ulcerative colitis and well tolerated in both conventional and high dosage (the latter equivalent to 5.5 g/day of sulphasalazine). In this study no distinct advantage in maintenance of remission has been found for the higher dose of balsalazide.

Randomised controlled trial of azathioprine withdrawal in ulcerative colitis.

OBJECTIVE: To determine whether azathioprine can prevent relapse in ulcerative colitis. DESIGN: One year placebo controlled double blind trial of withdrawal or continuation of azathioprine. SETTING: Outpatient clinics of five hospitals. SUBJECTS: 79 patients with ulcerative colitis who had been taking azathioprine for six months or more. Patients in full remission for two months or more (67), and patients with chronic low grade or corticosteroid dependent disease (12) were randomised separately. 33 patients in remission received azathioprine and 34 placebo; five patients with chronic stable disease received azathioprine and seven placebo. MAIN OUTCOME MEASURE: Rate of relapse. Relapse was defined as worsening of symptoms or sigmoidoscopic appearance. RESULTS: For the remission group the one year rate of relapse was 36% (12/33) for patients continuing azathioprine and 59% (20/34) for those taking placebo (hazard rate ratio 0.5, 95% confidence interval 0.25 to 1.0). For the subgroup of 54 patients in long term remission (greater than six months before entry to trial) benefit was still evident, with a 31% (8/26) rate of relapse with azathioprine and 61% (17/28) with placebo (p less than 0.01). For the small group of patients with chronic stable colitis (six were corticosteroid dependent and six had low grade symptoms) no benefit was found from continued azathioprine therapy. Adverse events were minimal. CONCLUSIONS: Azathioprine maintenance treatment in ulcerative colitis is beneficial for at least two years if patients have achieved remission while taking the drug. Demonstration of the relapse preventing properties of azathioprine has implications for a large number of patients with troublesome ulcerative colitis, who may benefit from treatment with azathioprine.

The rectal mucosa-associated microflora in patients with ulcerative colitis.

The rectal mucosa-associated flora (MAF) of patients with ulcerative colitis has been studied in 25 patients with newly diagnosed disease, 20 with relapse of existing disease, and 44 who were in remission. Patients with active disease were re-examined twice during treatment. The MAF was simpler and less dense than the microflora of faeces. Obligate anaerobes usually predominated in the MAF although the ratio of obligate anaerobes to facultative species was lower than that found in faeces. Viable counts of the total flora and of its constituent genera varied considerably between patients. Counts of the total flora, of obligate anaerobes (including bifidobacteria, eubacteria and clostridia), and facultative organisms and micro-aerobes (enterobacteria and lactobacilli) were reduced in patients with active disease compared with those with inactive disease; corresponding carriage rates were also lower. Counts and carriage rates increased during treatment and approached those found in quiescent disease. The alterations in the MAF were especially marked in patients experiencing their first attack of ulcerative colitis. The relationship between these alterations and the aetiology and pathogenesis of this disease remains unclear.