Digestive system diseases

Editorial Confusion about secondary prevention for bowel cancer: resolving issues at the front line MJA 1999; 170: 102-103 An effective, clearly enunciated national policy is needed for secondary prevention (screening and surveillance) of bowel cancer in Australia. Bowel cancer meets the World Health Organization criteria for screening, and is the commonest internal malignancy affecting both sexes in Australia, causing more deaths than any other cancer except lung cancer.1Three randomised controlled trials have shown that screening average-risk populations (aged 50 years and over) by the crudest of faecal occult blood tests (Hemoccult) is effective in reducing population mortality from bowel cancer on an intention-to-screen basis.1 Furthermore, calculations of cost-effectiveness using Australian cost data and screening outcomes of the poorly specific rehydrated Hemoccult test show that screening for bowel cancer is about as cost effective as screening for breast cancer.2Given that neither mortality from bowel cancer nor cancer stage at diagnosis has improved in various Australian States,3 we can assume that current secondary prevention activities are only minimally effective. Indeed, the incidence of bowel cancer continues to rise in men.3 Why are we not conducting screening and surveillance? Why are we missing out on their demonstrable benefit? From a national perspective, two key issues arise: How should we implement screening to reduce population bowel cancer mortality rates?; and While this question is being answered, what is reasonable action for individuals interested in being screened or for those at risk of bowel cancer? Unfortunately, failure to separate these two issues has led to confusion and misunderstanding of promulgated guidelines. The issue of an effective population screening program was addressed in the Australian Health Technology Advisory Committee (AHTAC) report released in April 1998.1 A recent editorial in the Journal called for the issues raised in that report to be addressed and resolved.4 The AHTAC report proposed "pilot and feasibility studies" to examine aspects of screening, such as logistics, choice of screening tool, risks, costs, acceptability, resources and education. It took an evidence-based approach and considered the issues from a population perspective. Early in 1998, the National Cancer Control Initiative submitted a proposal to government seeking funds for pilot and feasibility studies in the general population. These funds have not yet been provided -- we will not have an effective program for the general population until results of pilot studies are available. In the meantime, doctors, and especially general practitioners (GPs), remain confused as to what is reasonable practice. Evidence for this confusion is presented by Sladden and Ward in this issue of the Journal.5 They found that many GPs are unaware of the evidence that screening is effective and are uncertain about intervals for testing, the age to start, and how to apply the screening/surveillance tools to an individual in a manner appropriate to the individual's risk profile. Few GPs are "highly likely" to recommend faecal occult blood screening (and presumably any other type of screening for bowel cancer) during a health check, even though we know that people who have biennial screening with Hemoccult have about a 40% reduction in risk of dying from bowel cancer.6Sladden and Ward point out that guidelines available in Australia are partly responsible for the confusion, because of their inconsistency in recommendations. This inconsistency arises partly because the issue is complex and the evidence is incomplete. Also, there is a failure to appreciate the difference in the guidelines between what is acceptable as a population strategy and what is reasonable for the individual who seeks screening. Given that the value of early-detection programs in average-risk individuals is supported by three randomised controlled trials of faecal occult blood test-based screening and by several case-control studies of flexible or rigid sigmoidoscopy screening, it is difficult to ignore the individual seeking help. The soon-to-be-promulgated Guidelines for the prevention, early detection and management of colorectal cancer of the National Health and Medical Research Council (NHMRC) and the Australian Cancer Network have been developed by a process of consensus, incorporating a national workshop and analysis of the evidence. These guidelines should provide a path through the confusion, provided they are endorsed and used by the medical colleges and other professional and educational bodies. They will also partly solve the problem of access to, and resourcing of, the colonoscopies needed for effective secondary prevention. Adherence to guidelines for colonoscopic surveillance of those at increased risk of bowel cancer might then free this limited resource for more effective deployment to a larger proportion of the population. The issues for the primary healthcare provider are complex: the GP needs to check the presence or absence of symptoms, profile the asymptomatic individual's risk, tailor the screening or surveillance program to that risk, and deal with the population's aversion to things anal or faecal. The media have been unhelpful in this respect, with little publicity given to bowel cancer.1,4 As pointed out by Sladden and Ward, GPs' actions might be suboptimal if they cannot immediately recall the necessary (rather complex) detail or access the services needed. When a GP considers that secondary prevention might be indicated, support in terms of education and access to carefully coordinated secondary prevention services should be provided by regional health services. The GP's role is important to the success of secondary prevention, whether it is part of a future coordinated mass program, or dealing with the individual seeking guidance or needing motivation. Clearer guidance will come from the NHMRC-Australian Cancer Network best practice guidelines. However, the continued rise in the incidence of bowel cancer and failure to lower its mortality will not be adequately controlled by such an ad hoc approach;7 population pilot studies are desperately needed, and so is government funding! Graeme P Young Professor of Gastroenterology, Flinders University of South Australia Head, Gastrointestinal Services, Flinders Medical Centre, and Repatriation General Hospital, Adelaide, SA Australian Health Technology Advisory Committee. Colorectal cancer screening. Canberra: Commonwealth Department of Health and Family Services, 1997. Salkeld S, Young G, Irwig L, et al. Cost-effectiveness analysis of screening by faecal occult blood testing for colorectal cancer in Australia. Aust J Public Health 1996; 20: 138-143. Bell JC, McCredie M, Coates MS, Armstrong B. Trends in colorectal cancer incidence and mortality in New South Wales 1973-1992. Med J Aust 1997; 166: 178-181. Collett JA, Olynyk JK. Colorectal cancer screening in average-risk, asymptomatic Australians [editorial]. Med J Aust 1998; 169: 14-15. Sladden MJ, Ward JE. Australian general practitioners' views and use of colorectal cancer screening tests. Med J Aust 1999; 170: 110-113. Hardcastle JD, Chamberlain JO, Robinson MHE, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996; 348: 1472-1477. Neugut AI, Young GP. Screening for colorectal cancer: an overview. In: Young GP, Levin B, Rozen P, editors. Prevention and early detection of colorectal cancer. London: WB Saunders, 1996: 357-368. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Graeme P Young

Research Australian general practitioners' views and use of colorectal cancer screening tests Michael J Sladden and Jeanette E Ward MJA 1999; 170: 110-113 For editorial comment, see Young Abstract - Introduction - Method - Results - Discussion - Acknowledgements - References - Author's details - - More articles on Gastroenterology Abstract Objectives: To determine general practitioners' (GPs) current beliefs, knowledge and self-reported practices of screening for colorectal cancer. Design and setting: Postal survey of national random sample of 1271 GPs in 1996. Outcome measures: GP views on effectiveness of faecal occult blood testing (FOBT) and flexible sigmoidoscopy in reducing premature death from colorectal cancer in "average-risk" patients (asymptomatic with no family history); views on frequency of tests and target group; use of these tests; and independent predictors of views and use. Results: Response rate was 67%. FOBT and flexible sigmoidoscopy were said to be effective as screening tests by 38% and 61% of GPs, respectively, but 30% and 25% were unsure. Independent predictors of belief in screening effectiveness were State of practice (for FOBT), male sex and awareness of Gut Foundation guidelines (for flexible sigmoidoscopy) and increasing age (for both). Most often chosen screening frequencies were every year for FOBT (29%), and five-yearly for flexible sigmoidoscopy (24%), although 19% and 26%, respectively, were unsure of the appropriate screening interval. Most often cited target group was people aged over 40 years with first-degree relatives with colorectal cancer: 63% of GPs would offer FOBT and 74%, flexible sigmoidoscopy. Fewer than 3% of GPs were likely to adopt an opportunistic approach to screening, yet 15% would be highly likely to recommend FOBT during a dedicated health check-up for a 58-year-old male patient, and 9% for a female patient. Conclusion: The absence to date of a coherent national policy on colorectal cancer screening is associated with wide variations in views and practice that are inconsistent with the available evidence. If GPs are to be involved in implementing population screening, national policy must be widely and effectively promulgated. Introduction The past decade has seen a saga of unfinished policy initiatives on screening for colorectal cancer in Australia. As early as 1990, screening by faecal occult blood test (FOBT) was being promoted for people with "average risk" of colorectal cancer, in the absence of convincing evidence or national policy.1 Since then, a range of bodies have produced guidelines with quite different recommendations, particularly for this "average risk" group.2-8 Examples are shown in Box 1. More recent among these was the 1997 report of the Australian Health Technology Advisory Committee (AHTAC) Working Party on Colorectal Cancer Screening. This working party was formed after a 1994 call for a national symposium to develop "recommendations about early detection of colorectal cancer" as part of Australia's national health goals and targets,9 and a 1995 deputation to the Commonwealth from the Australian Cancer Network. The Network recommended pilot projects of screening and, if these were successful, implementation of national screening. AHTAC found that FOBT was effective in reducing mortality from colorectal cancer in the average-risk population (defined as the "well population aged over 50") and recommended studies to determine the effectiveness of different screening strategies, particularly how best to involve general practitioners (GPs). Meanwhile, in 1998, another set of draft guidelines, not yet nationally endorsed, was circulated by the Clinical Oncological Society of Australia and the Australian Cancer Network.8 Despite the unresolved status of national policy, research has continued to involve Australian GPs overtly or covertly in colorectal cancer screening.10-14 Most recently, a survey of Perth GPs reported high uptake of this screening.15 As no national studies have been conducted, we designed a postal survey to assess GPs' perceptions of the effectiveness of screening for colorectal cancer and self-reported levels of screening. Method GP sample and survey administration A covering letter, questionnaire and reply-paid envelope were mailed in May 1996 to a national random sample of 1271 GPs, as described elsewhere.16 Standardised response-aiding strategies were used to follow up non-respondents.16 Questionnaire Questions on colorectal cancer screening were part of a larger questionnaire on current status of cancer screening in general practice. Respondents were asked to tick the response that matched their views on: Effectiveness of FOBT and flexible sigmoidoscopy in reducing premature deaths from colorectal cancer in "average risk" patients (ie, asymptomatic patients with no family history); Frequency of screening; Who should be screened; Likelihood of their initiating a discussion about FOBT or flexible sigmoidoscopy with a well 58-year-old male, and next female, patient during non-urgent consultations for ear syringing as well as during scheduled health check-ups; and Usefulness of three guidelines available at the time of the surveys (first three items in Box 1). The final section of the questionnaire included eight sociodemographic questions. Data analysis Descriptive, cross-tabulation and logistic regression analyses were performed with SPSS for Windows 7.17 Logistic regression analyses were performed to determine independent predictors of knowledge and practice outcomes. Fourteen potential predictors were considered: GP's sex; age; State; full- or part-time practice; practice type (solo or group); membership of a Division of General Practice; Royal Australian College of General Practitioners (RACGP) affiliation; membership of the Australian Medical Association; personal history of cancer; family history of cancer; awareness of RACGP guidelines; Australian Gastroenterology Institute/Australian Cancer Society guidelines; and Gut Foundation of Australia (GFA) guidelines; and practice location (metropolitan or other18). All independent variables were included in the full model. A further variable -- belief that FOBT/flexible sigmoidoscopy is an effective screening test -- was included in the model to predict behaviour. A backwards stepwise modelling strategy was used to identify significant independent variables, whereby all dependent variables were initially included and non-significant terms were progressively eliminated. Significance was assessed using the Wald chi-squared statistic. Results We received 855 usable questionnaires from 1271 eligible GPs (67% response rate). The response rate for women (75%) was significantly higher than that for men (63%) (chi-squared = 15.4, 1 df, P < 0.001), but did not vary with age, vocational registration status, RACGP affiliation, or practice size and location. GP views about screening GP views about the effectiveness of screening for colorectal cancer in preventing premature deaths are shown in Box 2. More GPs believed flexible sigmoidoscopy to be effective (61%) than believed FOBT to be effective (38%), but there was substantial uncertainty about both screening tests, with 25% and 30% of GPs unsure. Independent predictors of believing either test to be effective are summarised in Figure 1. For FOBT, these comprised increasing GP age and State of practice (specifically, South Australia). For flexible sigmoidoscopy, they comprised increasing GP age, male sex, and awareness of the Gut Foundation guidelines (which favour screening). GPs' views on appropriate screening frequencies and target groups are shown in Box 2. Most often chosen frequencies were every year for FOBT (29%), and five-yearly for flexible sigmoidoscopy (24%). However, 19% and 26%, respectively, were unsure of the appropriate screening interval. The most often cited target group was people aged over 40 years with first-degree relatives with colorectal cancer: 63% of GPs would offer FOBT and 74%, flexible sigmoidoscopy. Self-reported practice Likelihood of suggesting colorectal cancer screening is shown in Box 3. Fewer than 3% of GPs were "highly likely" to adopt an opportunistic approach to colorectal cancer screening for a 58-year-old patient (by either test) or to recommend flexible sigmoidoscopy screening during a dedicated health check-up. More would be "highly likely" to recommend FOBT during a dedicated health check -- 15% if the patient was a man and 9% if a woman. This sex difference was significant (McNemar's chi-squared = 43.7, 1 df, P < 0.0001). Independent predictors of being "highly likely" to include FOBT in a health check-up are shown in Figure 2. They comprised increasing GP age, State of practice, and belief in the effectiveness of the tests. Usefulness ratings of guidelines available at the time of the survey are shown in Box 4. While RACGP, AGI/ACS and GFA guidelines were rated as "very" or "somewhat" useful by 33%, 50% and 45% of respondents, respectively, they were unable to be recalled by 52%, 35% and 41%. Discussion Our study suggests considerable confusion about colorectal cancer screening at the "front line" of general practice. About a third of respondents believed that FOBT was an effective screening test in average-risk individuals, while two-thirds believed this of flexible sigmoidoscopy. These beliefs are inconsistent with the evidence available at the time of our study: level II (randomised controlled trial) evidence19 that FOBT reduced colorectal cancer mortality, but only level III (case-control study) evidence20 supporting flexible sigmoidoscopy. A wide range of responses were given about appropriate screening frequency. This is not surprising, as the three guidelines available at the time offered different and contradictory advice, and none met the criteria for being systematically evidence-based. Further confusion is likely if yet more guidelines8 are published that contradict the evidence-based AHTAC guidelines.7Far fewer GPs reported using the screening tests than reported they were effective; most respondents did not use the tests. This discordance was greater for sigmoidoscopy than for FOBT. Again, it is likely that the lack of clarity and the variation between guidelines, as well as availability of conflicting information and educational material, have caused uncertainty among GPs, with concomitant inconsistency in their behaviour. Perhaps FOBT is used more often than sigmoidoscopy because it is easier to arrange. Increasing GP age and physician belief in screening effectiveness independently predicted self-reported provision of screening. South Australian GPs were more likely to advocate screening, perhaps because of research studies and community-based initiatives in that State.10 GPs also favoured screening men rather than women for colorectal cancer. Sex bias not been reported previously in colorectal cancer screening, and may reflect the higher incidence of colorectal cancer among men.21 Alternatively, perhaps GPs place a lower priority on colorectal cancer screening in women, for whom cervical and breast cancer screening are widely performed, but a higher priority in men, for whom there is, as yet, no "male cancer" screening of proven benefit. National levels of self-reported use of screening tests were less than previously reported,15,22,23 although the higher levels in South Australia were consistent with earlier data.10 GPs' wider endorsement of screening for "above-average-risk" individuals with first-degree relatives with colorectal cancer (63%-74%) was similar to the levels found in recent studies (80%-94% GP support),10,15 but considerably higher than in a similar 1982 study (23% GP support).22 Screening of relatives is apparently becoming more acceptable. Usefulness and recall of guidelines was low, similar to other recent findings.15 Our results suggest an urgent need for a national colorectal cancer screening policy. As GPs remain the most respected source of health information,24 it is vital they have access to timely and accurate information. The AHTAC report, released in 1998, was necessary but insufficient. If GPs are to be involved in implementation of colorectal cancer population screening (which, by definition, will target average-risk individuals), strategies are needed to inform them of the importance of screening and to facilitate appropriate changes in behaviour. When there has been a concerted effort to communicate agreed policy to Australian GPs (eg, about mammographic screening), uniformity of GP views has been achieved.25 However, when evidence is lacking (eg, for clinical breast examination),25 or State-based initiatives are patchy,26 it appears that GPs differ considerably in their views of screening effectiveness and self-reported behaviour. Our study concentrated on screening average-risk individuals, for which previous guidelines have been confusing, non-evidence based and at variance with each other. Most guidelines distinguish between screening for average-risk and above-average-risk individuals, generally recommending colonoscopic screening for above-average-risk groups (eg, those with familial adenomatous polyposis and hereditary non-polyposis colorectal cancer). Clearly, strategies for effective evidence-based screening of above-average-risk groups must also be promoted. Thus, our results reveal our failings to date as an organised healthcare system to provide GPs with timely, consistent and evidence-based health policy, as they and their patients deserve. Our study provides a baseline against which the effectiveness of future dissemination of colorectal cancer screening policy may be measured. Acknowledgements A Commonwealth General Practice Evaluation Program seeding grant funded this study. We thank the GPs who participated in our research with no financial incentive, Phoebe Holt for contributing to questionnaire design, and Tracey Bruce for diligent survey administration. The study was approved by the Ethics Committee of the Royal Prince Alfred Hospital, Sydney, NSW. References Woodward A, Weller D. Colorectal cancer: implications of mass screening for public health. Med J Aust 1990; 153: 81-88. Guidelines for screening for colorectal cancer. Sydney: Australian Gastroenterology Institute, 1991. Australian Cancer Society. National cancer prevention policy, 1993. Sydney: Australian Cancer Society, 1993. Bolin T, Collopy B, Cowen A, et al. Colorectal cancer: prevention, diagnosis and treatment. Sydney: The Gut Foundation and Colorectal Surgical Society of Australia, 1993. Goulston K, St John DJ, Bokey L, et al. Guidelines for early detection, screening and surveillance for colorectal cancer. 2nd ed. Sydney: Australian Gastroenterology Institute and Australian Cancer Society, 1994. Guidelines for preventive activities in general practice. 3rd ed. Sydney: Royal Australian College of General Practitioners, 1994. Australian Health Technology Advisory Committee (Standing Committee of the National Health and Medical Research Council). Colorectal cancer screening. Canberra: Commonwealth Department of Health and Family Services, 1997. Clinical Oncological Society of Australia and Australian Cancer Network. Guidelines for the prevention, early detection and management of colorectal cancer. Draft 3. June 1998. Better health outcomes for Australians. Canberra: National Health Goals and Targets Section, Department of Human Services and Health, 1994. Cockburn J, Thomas R, McLaughlin S, et al. Acceptance of screening for colorectal cancer by flexible sigmoidoscopy. J Med Screen 1995; 2: 79-83. Rae L. Community screening for colorectal cancer in north-eastern New South Wales, 1987-1996. Med J Aust 1998; 168: 382-385. King J, Fairbrother G, Thompson C, Morris D. Colorectal cancer screening: optimal compliance with postal faecal occult blood test. Aust N Z J Surg 1992; 62: 714-719. King J, Fairbrother G, Thompson C, Morris D. Influence of socioeconomic status, ethnicity and an educational brochure on compliance with a postal faecal occult blood test. Aust N Z J Public Health 1994; 18: 87-92. Olynyk J, Aquilia S, Fletcher D, Dickinson J. Flexible sigmoidoscopy screening for colorectal cancer in average-risk subjects: a community-based pilot project. Med J Aust 1996; 165: 74-76. Olynyk J, Aquilia S, Platell C, et al. Colorectal cancer screening by general practitioners: comparison with national guidelines. Med J Aust 1998; 168: 331-334. Ward J, Bruce T, Holt P, et al. Labour-saving strategies to increase response rates in general practice surveys. Aust N Z J Public Health 1998; 22: 394-396. Statistical Package for the Social Sciences. SPSS for Windows 7.5.1. Chicago (Ill): SPSS Inc, 1996. Commonwealth Department of Primary Industries and Energy and Commonwealth Department of Human Services and Health. Rural, Remote and Metropolitan Areas Classification: 1991 Census edition. AGPS, Canberra: 1994. Mandel J, Bond J, Church T, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993; 328: 1365-1371. Selby J, Friedman G, Quesenberry C, Weiss N. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992; 326: 653-657. Jelfs P, Coates M, Giles G, et al. 1996 Cancer in Australia 1989-1990 (with projections to 1995). Canberra: Australian Institute of Health and Welfare (Cancer Series No. 5). Macrae FA, Hill DJ, Dent O, et al. Colorectal cancer: knowledge and attitudes of doctors in Victoria. Aust N Z J Med 1982; 12: 278-283. Rolfe I, Pearson S. Screening recommendations in general practice: a survey of graduates from different medical schools. Med J Aust 1996; 165: 14-17. Cumming R, Barton G, Fahey P, et al. Medical practitioners and health promotion: results from a community survey in Sydney's western suburbs. Community Health Stud 1989; 13: 294-301. Young J, Ward J, Holt P. Breast cancer screening in Australian general practice: results of a national survey. Med J Aust 1998; 169: 364-368. Ward J, Donnelly N, Holt P. Impact in general practice of the policies of the organised approach to preventing cancer of the cervix. Aust N Z J Public Health 1998; 22: 336-341. (Received 25 Jun, accepted 28 Oct, 1998) Author's details Division of Community and Rural Health, University of Tasmania, Hobart, TAS. Michael J Sladden,FRACGP, MAppEpid, Honorary Senior Lecturer. Needs Assessment and Health Outcomes Unit, Central Sydney Area Health Service, Sydney, NSW. Jeanette E Ward, PhD, FAFPHM, Director. Reprints will not be available from the authors. Correspondence: Dr M J Sladden, Division of Community and Rural Health, PO Box 252-33, University of Tasmania, Hobart, TAS 7001. Email: M. Sladden@utas.edu.au Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> Figure 1 : Independent predictors of general practitioners (GPs) reporting that faecal occult blood testing or flexible sigmoidoscopy is effective in reducing premature deaths from colorectal cancer. Back to text Figure 2 : Independent predictors of general practioners (GPs) reporting they would be "highly likely" to discuss faecal occult blood testing during a deicated health check-up with a 58-year-old patient. (Adjusted odds ratios with 95% confidence intervals are available from the authors.)Back to text 1: Recommendations about colorectal cancer screening for average-risk* people Gut Foundation of Australia (1993)4 Screening by annual FOBT; consider 3-5-yearly flexible sigmoidoscopy Australian Gastroenterology Institute/Australian Cancer Society (1994) 5 Routine screening not recommended; can be performed at patient request Royal Australian College of General Practitioners (1994)6 Screening not recommended Australian Health Technology Advisory Committee (1997)7 Screening by FOBT; research required to determine method and frequency Clinical Oncological Society of Australia/Australian Cancer Network (draft 1998)8 Screening by annual FOBT; consider 5-yearly flexible sigmoidoscopy FOBT=faecal occult blood test. *Asymptomatic people aged over 50 years with no family history Back to text Back to text Back to text Back to text

Michael J Sladden · Jeanette E Ward

Paediatric rotavirus gastroenteritis: where to now in prevention and treatment? While we await a preventive vaccine, we should concentrate on appropriate management, which means avoiding medications and giving dilute fluids to counter dehydration MJA 1998; 169: 241-242 Rotavirus is a major cause of gastroenteritis affecting young children worldwide. In this issue of the Journal, Carlin and colleagues present data which suggest that, of the approximately 20 000 children under five years admitted to hospital with acute gastroenteritis in Australia annually (a rate of 15/1000 per year), rotavirus is responsible in 50%.1 This accords with a recent New South Wales study suggesting that 56% of hospitalisations for acute gastroenteritis in this age group could be attributed to rotavirus.2The virus was first identified in 1973 by Bishop and coworkers at the Royal Children's Hospital, Melbourne, when they used electron microscopy to examine duodenal biopsies from infants admitted to hospital with severe acute non-bacterial gastroenteritis.3 Since that time, rotavirus has also been shown to be a cause of acute gastroenteritis in the young of a wide range of wild and domestic mammals. The virus, a member of the family Reoviridae, can be classified into serogroups A-G, and most human infections are caused by serogroup A. Routine diagnosis is based on rapid detection of group A antigen in faeces, generally by latex agglutination or enzyme immunoassay. In temperate climates, rotavirus infection occurs all year round, with very pronounced annual winter-spring peaks in incidence. The major epitope associated with a protective immune response is the viral outer capsid glycoprotein VP7. In mammalian rotavirus strains, monoclonal antibodies can be used to differentiate this protein into 10 serotypes, of which four, G1 to G4, are responsible for most cases of severe disease in young children. The rotavirus genome comprises 11 segments of double-stranded RNA, which readily allows genetic reassortment when coinfection is induced in vitro with strains of differing serotypes from one or more species.4 Approaches to vaccine development have concentrated on G1 rhesus strains, strains of human neonatal origin and tetravalent rhesus-human reassortants expressing G1-G4 serotypes. Large-scale clinical trials to date have shown advantages in the tetravalent vaccine candidates in protective efficacy,4 and it is likely that an oral tetravalent rhesus-human reassortant rotavirus vaccine will be approved in Australia in the next 1-2 years. Randomised controlled trials of this vaccine given as three oral doses between six weeks and six months of age were conducted among both urban and Native American populations in the United States, and in Finland. These trials showed protective efficacies of 49%-66% against any rotavirus gastroenteritis and 69%-100% against very severe infection.5-7 The vaccine was found to be relatively safe, with adverse reactions largely limited to fever and irritability after the first dose -- one-third of children had fever over 38oC, while 3% had fever over 39oC.8 Another approach to preventing rotavirus gastroenteritis is passive immunisation -- giving oral preparations containing high-titre rotavirus antibodies derived from the colostrum of immunised cows. One study showed a marked reduction in the incidence of hospital-acquired rotavirus infection when hospitalised children were given a hyperimmune bovine colostrum preparation,9 and further trials are under way to assess the value of community use. Use of either active or passive immunisation may be of particular value in children aged under three years attending long- daycare, as rotavirus infection in this group causes substantial morbidity and family disruption.10 Although preventing rotavirus gastroenteritis has obvious appeal, our medium-term focus will continue to be on managing children with acute gastroenteritis. Carlin et al note substantial differences in hospital admission rates between Australian States and raise the possibility that there are variations in hospital admission policies or practices.1 Other local data have shown that most children admitted to two NSW children's hospitals have only a minor degree of dehydration.11,12 In an editorial comment on one of these NSW studies, Barnes indicated "continuing concern as to why so many mildly dehydrated children are admitted to Australian hospitals and why so many of them receive intravenous therapy".13 We have limited information on the management of gastroenteritis in the community and in hospital emergency departments. Most of the data are based on extrapolation from children who have been admitted to hospital. Preadmission management is suboptimal -- antibiotics, antiemetics or antidiarrhoeals are prescribed for more than 20%.11,12 The use of oral rehydration solution in the community is low, although most children are offered appropriately diluted clear fluids.11,12 While hospitalised children with gastroenteritis may not accurately reflect treatment practices in the community, there remains a disparity between management guidelines14 and actual practice. Treatment of gastroenteritis in the community should include continued breastfeeding in infants or increased fluids in older children. Either oral rehydration solution or appropriately diluted fluids are acceptable. Children should be allowed to return to their usual diet if they are hungry. Regular review of the child's progress, with particular focus on fluid balance, should be regarded as good clinical practice and not as overservicing. By contrast, medications are rarely required, may be harmful and should be avoided. Undiluted cordial, fruit juice or carbonated drinks (such as flat lemonade) are hyperosmolar solutions and pose the danger of exacerbating the diarrhoea. The prospect that a future rotavirus vaccine, if widely used, will have a major beneficial impact is exciting. Coupled with this is the need to deliver more effective clinical management of acute gastroenteritis in the community. Mark J Ferson Director, Public Health Unit, South Eastern Sydney Area Health Service and Staff Specialist in Public Health, Sydney Children's Hospital, Sydney, NSW Richard Henry John Beveridge Professor, School of Paediatrics, Sydney Children's Hospital and University of New South Wales, Sydney, NSW Carlin JB, Chondros P, Masendycz P, et al. Rotavirus infection and rates of hospitalisation for acute gastroenteritis in young children in Australia, 1993-1996. Med J Aust 1998; 169: 252-256. Ferson MJ. Hospitalisations for rotavirus gastroenteritis among children under five years of age in New South Wales. Med J Aust 1996; 164: 273-276. Bishop RF, Davidson GP, Holmes IH, Ruck BT. Virus particles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis. Lancet 1973; ii: 1281-1283. Kapikian AZ, Hoshino Y, Chanock RM, Perez-Schael I. Jennerian and modified Jennerian approach to vaccination against rotavirus diarrhea using a quadrivalent rhesus rotavirus (RRV) and human-RRV reassortant vaccine In: Chiba S, Estes MK, Nakata S, Calisher CH, editors. Viral gastroenteritis. Vienna: Springer-Verlag, 1996: 163-175. Rennels MB, Glass RI, Dennehy PH, et al. Safety and efficacy of high-dose rhesus-human reassortant rotavirus vaccines -- report of the National Multicenter Trial. Pediatrics 1996; 97: 7-13. Toensuu J, Koskenniemi E, Pang X-L, Vesikari T. Randomised placebo-controlled trial of rhesus-human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis. Lancet 1997; 350: 1205-1209. Santosham M, Moulton LH, Reid R, et al. Efficacy and safety of high-dose rhesus-human reassortant rotavirus vaccine in Native American populations. J Pediatr 1997; 131: 632-638. Joensuu J, Koskenniemi E, Vesikari T. Symptoms associated with rhesus-human reassortant rotavirus vaccine in infants. Pediatr Infect Dis J 1998; 17: 334-340. Davidson GP, Whyte PBD, Daniels E, et al. Passive immunisation of children with bovine colostrum containing antibodies to human rotavirus. Lancet 1989; ii: 709-712. Ferson MJ, Stringfellow S, McPhie K, et al. A longitudinal study of rotavirus infection in child-care centres. J Paediatr Child Health 1997; 33: 157-160. Loughlin EV, Notaras E, McCullough C, et al. Home-based management of children hospitalized with acute gastroenteritis. J Paediatr Child Health 1995; 31: 189-191. Elliott EJ, Backhouse JA, Leach JW. Pre-admission management of acute gastroenteritis. J Paediatr Child Health 1996; 32: 18-21. Barnes GL. Oral rehydration solutions in gastroenteritis before and after admission to hospital. J Paediatr Child Health 1996; 32: 16-17. Gastroenteritis. A guide for parents and caregivers. Sydney: Australian Gastroenterology Institute, 1996. - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Mark J Ferson · Richard Henry

Rotavirus infection and rates of hospitalisation for acute gastroenteritis in young children in Australia, 1993-1996 John B Carlin, Patty Chondros, Paul Masendycz, Helen Bugg, Ruth F Bishop and Graeme L Barnes For editorial comment, see Ferson MJA 1998; 169: 252-256 Abstract - Introduction - Methods - Results - Discussion - Acknowledgments - References - Authors' details - Figure 1 - Figure 2 - - - ©MJA1998 Abstract Objective: To determine rates of hospitalisation of young children for acute gastroenteritis in Australia, and to estimate the proportion of these admissions caused by rotavirus infection. Design: Analysis of hospital admission records, and parallel, prospectively collected data on rotavirus-positive admissions. Setting: Hospitals admitting young children in all Australian States and Territories in 1993-1996. Patients: All children under five years admitted to hospital for acute gastroenteritis (International Classification of Diseases, ninth revision principal diagnosis codes 003.0, 004.0-009.3 and 558.9). Main outcome measures: Rate of hospital admission per 1000 children per year by State, and the proportion of admissions caused by rotavirus infection. Results: There were almost 20 000 hospital admissions annually in Australia for acute gastroenteritis in children under five years, at an average rate of 15/1000. An estimated 50% of these were attributable to rotavirus infection, implying a rate of hospitalisation for rotavirus-related gastroenteritis of 7.5/1000/year. Among children under two years this rate was 11.6/1000. Rotavirus incidence rates generally followed a typical seasonal pattern in temperate regions of the country, with sharp peaks in mid to late winter. Rates of hospitalisation varied markedly, even between States with apparently similar patterns of disease, while the incidence in the Northern Territory was 3-5 times higher than other States. Conclusions: Rotavirus-related gastroenteritis is a major cause of hospital admissions in young children, and large savings to the healthcare system are possible if it can be prevented at reasonable cost. Variation in treatment practices between States may be worth studying in greater detail as another source of potential savings. MJA 1998; 169: 252-256 Introduction Rotavirus is a major cause of severe gastroenteritis in young children. Although discovered only 25 years ago,1 the role of this virus in the huge burden of diarrhoeal disease in developing countries was recognised quickly, and in 1985 it was estimated to be responsible for 870 000 deaths annually.2 In developed countries, mortality from gastroenteritis is low, but many studies have documented the large burden of morbidity caused by rotavirus.3-7Precise estimates of rotavirus-related morbidity are difficult to obtain from routine hospital data because stool samples for microbiological testing are not obtained from all children admitted to hospital with diarrhoea. Even when testing is performed, the findings may not be recorded or coded in the medical record. There was no specific category in the International Classification of Diseases, ninth revision (ICD-9-CM) for rotavirus diarrhoea until 1993, and since then the specified code (008.61) has not been used consistently. However, many studies have shown that at least 30% of hospital admissions for acute gastroenteritis in young children are the result of rotavirus infection and, further, that the incidence of rotavirus infection has a distinctive cyclical pattern with a peak in winter (this is unique to rotavirus among all major pathogens associated with gastroenteritis).3,4,6,8-10 While other Australian studies have examined aspects of rotavirus gastroenteritis,5,11 there are no national population-based estimates of the incidence of hospital admission for acute gastroenteritis in young children. Such estimates are important in assessing preventive measures, and in evaluating the cost-effectiveness of rotavirus vaccines currently under development.12,13 We aimed to provide the first national data on rates of hospitalisation of young children for acute gastroenteritis in Australia, and to estimate the proportion of these admissions that could be ascribed to rotavirus infection. Our results will be used in a later study to estimate the cost-effectiveness of rotavirus vaccination. Methods State and Territory health departments provided computer files with unidentified records for the years 1993 through 1996 of all hospital admissions of children under the age of five with a principal diagnosis in the medical record of acute gastroenteritis. In our analysis, we combined data from the Australian Capital Territory with those from New South Wales. Acute gastroenteritis was identified as ICD-9-CM codes in the range 003-009 (covering infectious gastroenteritis of various known and unknown origins) or code 558.9 ("other and unspecified noninfectious gastroenteritis"). This last code was included for consistency with other studies in the expectation that it might comprise a substantial number of cases of infectious gastroenteritis. Similar files of admission records were obtained from participating paediatric hospitals in each of the States (see Box 1). Records from the Royal Children's Hospital (RCH), Melbourne, and Princess Margaret Hospital (PMH), Perth, also included an identifying hospital record number. 1: Participating hospitals Royal Children's Hospital, Melbourne (VIC) Princess Margaret Hospital, Perth (WA) Women's and Children's Hospital, Adelaide (SA) Alice Springs Hospital (NT) Royal Darwin Hospital (NT) Royal Hobart Hospital (TAS) Sydney Children's Hospital (formerly Prince of Wales Children's Hospital) (NSW) New Children's Hospital, Sydney (Royal Alexandra Hospital for Children) (NSW) Westmead Hospital, Sydney (NSW) Royal Brisbane Hospital (QLD) Microbiology departments at participating hospitals were asked to forward all rotavirus-positive faecal specimens obtained from children under five years who were admitted for acute gastroenteritis to laboratories at RCH, where rotavirus infection was confirmed by enzyme immunoassay.14 All participating hospitals provided specimens over the entire study period, except that Westmead Hospital participated in the study for the first two years only, and was replaced by Sydney Children's Hospital in 1995. Seasonal, temporal, and geographic variation in strains of rotaviruses will be reported elsewhere. We estimated the proportion of gastroenteritis admissions that were caused by rotavirus infection both by direct and indirect means. The direct method involved a linked analysis of admissions and rotavirus data. Admission and laboratory records from RCH (Melbourne) and PMH (Perth) were linked by means of hospital unit record number and date of admission/date of specimen, thus identifying the proportion of admissions that we could directly confirm as involving rotavirus infection. This analysis was supplemented with information from each hospital's pathology records, as it became clear that not every rotavirus-positive specimen was being sent on to our laboratory (usually owing to insufficient size of samples). Further, it was possible to omit patients for whom no faecal test was performed, to give a more appropriate denominator for estimating the fraction admitted because of rotavirus infection (calculated as rotavirus fraction = number of admissions with positive rotavirus test result/number of admissions with faecal specimen tested). The indirect statistical estimation of the rotavirus fraction and the rationale behind this method are described in Box 2. The study was approved by ethics committees in each of the participating hospitals. 2: Statistical estimation of the rotavirus fraction We assumed (i) that rotavirus is the only major cause of childhood gastroenteritis admissions that shows significant seasonal variation; and (ii) that the total number of admissions due to rotavirus in a State is a constant multiple of the number seen in our participating hospital(s). Thus, total admissions per month were expressed as the sum of a constant number (representing non-rotavirus causes) and varying numbers of rotavirus admissions. The resulting linear regression model for the number of admissions in a State in each month was used to estimate the rotavirus fraction (the proportion of hospital admissions for acute gastroenteritis resulting from rotavirus infection). This is shown mathematically below, where: Ni = number of acute gastroenteritis admissions in the State in month i; ni = number of "rotavirus-positive" admissions in the State's participating (index) hospital(s); = monthly number of admissions statewide not caused by rotavirus; and = scaling factor relating the number of "rotavirus-positive" admissions in the State to that in the index hospital(s). The regression model (in which i = random error) is: Ni = + ni + i , which leads to: We followed earlier practice4,5 and used ordinary least squares to estimate , despite the fact that the model does not fit the usual assumptions of linear regression (in particular, the variance of i cannot be expected to be constant). As the assumption that there is perfect correlation between rotavirus incidence recorded at the index hospital and total rotavirus numbers at all hospitals in the State is inevitably untrue, there will be an underestimation of in this model, and consequently some underestimation of the rotavirus fraction. On the other hand, if the assumption that rotavirus is the only agent responsible for seasonal variation is wrong, then the estimation may be biased in either direction. The estimate is also potentially subject to other biases relating to the completeness and regularity of coverage of the contributed rotavirus samples. These biases are likely to outweigh random error, so that conventional confidence intervals would not provide a reliable indicator of uncertainty. Results Total numbers and estimated rates of acute gastroenteritis admissions are shown in Box 3. Of all admissions, 65.7% involved children under the age of two years, with approximately equal numbers in each of the first two years of life, and declining numbers in each of the subsequent three years to age five. The age breakdown was similar in all States except the Northern Territory, where a substantially larger proportion were aged under two (86.1%). Length of stay was also considerably longer in the Northern Territory. There were slightly more boys than girls (53.1% overall), consistent across all States. Of all admissions, 29.4% were coded 558.9, although this proportion declined sharply over the four years of the study as coding practices apparently changed. 3: Acute gastroenteritis in children aged less than five years, 1993-1996. Number and rate of hospital admissions, rate ratio relative to the Victorian rate, and average length of stay (95% confidence intervals in parentheses) State or TerritoryAverage annual admissionsAnnual rate per 1000 children under 5 yearsRate ratio relative to VictoriaAnnual rate per 1000 children under 1 yearAnnual rate per 1000 children aged 1-2 yearsAverage length of stay Victoria29159.2 (9.0-9.3)1.00 14.6 (14.1-15.1)14.4 (13.9-14.8) 1.93 days (1.90-1.96) Tasmania3199.3 (8.8-9.8) 1.01 (0.96-1.07) 15.0 (13.6-16.4) 15.1 (13.7-16.6) 1.79 days (1.71-1.87) Western Australia178614.2 (13.9-14.5) 1.55 (1.51-1.60) 25.3 (24.3-26.2) 24.9 (24.0-25.9) 3.13 days (3.03-3.23) Queensland377316.0 (15.7-16.2) 1.74 (1.70-1.79) 24.0 (23.3-24.7) 26.4 (25.6-27.1) 2.15 days (2.11-2.18) New South Wales*786617.1 (16.9-17.3) 1.87 (1.83-1.91) 25.5 (25.0-26.0) 27.5 (27.0-28.1) 2.11 days (2.09-2.13) South Australia189519.2 (18.8-19.7) 2.10 (2.04-2.16) 32.0 (30.7-33.2) 30.7 (29.5-31.9) 2.09 days (2.03-2.15) Northern Territory85449.8 (48.2-51.4) 5.44 (5.24-5.65) 106.2 (101.0-111.3) 108.1 (102.9-113.3) 9.18 days (8.88-9.47) Total1940815.0 (14.9-15.1) 23.9 (23.6-24.2) 25.0 (24.7-25.3) * Including Australian Capital Territory. Box 4 shows the temporal pattern of all admissions and of rotavirus admissions in index hospitals in the five largest States and the Northern Territory. The seasonal peaks in the eastern States (New South Wales, Victoria, Queensland, and South Australia) were generally coincident and occurred regularly in the colder months from July to September (except for the unusual final year in South Australia). In contrast, the weaker and less regular peaks in Western Australia occurred earlier than in the eastern States, and there was no discernible seasonal pattern in the Northern Territory. Even where the seasonal pattern was less distinct, the peaks in statewide admissions were reflected in peaks in the numbers of rotavirus- positive specimens. 4: Monthly incidence of hospital admission for acute gastroenteritis in children under five years of age in Australian mainland States and the Northern Territory, 1993-96 (solid line) and number of rotavirus-positive specimens received from participating hospitals in that State, rescaled from the hospital to the State level (dashed line), by the "regression method" For the data linkage method, among 1732 children admitted for whom a specimen was tested, we received 767 rotavirus-positive specimens from RCH (Melbourne) and found another 205 admissions with hospital records showing a positive rotavirus test, giving an estimated rotavirus fraction of 56%. The corresponding totals from PMH (Perth) were 1631, 626 and 161, respectively, giving a rotavirus fraction of 49%. Regression estimates of the rotavirus fraction ranged from a low of 22% for the Northern Territory (based on a total of 598 rotavirus-positive specimens) to a high of 41% for Victoria (984 specimens). When data from all States were combined, the correlation between rotavirus numbers and admissions increased, because a more accurate representation of the relationship between total admissions and rotavirus numbers in participating hospitals was obtained by pooling. The resulting estimated rotavirus fraction was 50% (based on 4634 specimens received). Separate estimates obtained for children aged under one year, one year to less than two years, and at least two years were 34%, 60% and 48%, respectively. Discussion This national four-year study has shown that there are almost 20 000 hospital admissions annually in Australia for acute gastroenteritis in children aged under five years -- an average rate of 15 per 1000, 50% of which appear to be attributable to rotavirus infection. The annual rate of hospitalisation for rotavirus-related gastroenteritis in children under five is therefore about 7.5 per 1000. Among children under two years, combining estimates for the two one-year age brackets, the corresponding rate is 11.6 per 1000, or just over one in every 100 children. Of the two methods we used to estimate the proportion of admissions that were caused by rotavirus, the method involving direct linkage of hospital admission records and stool specimen tests is likely to be the more accurate. Estimates of 56% (Melbourne) and 49% (Perth) were obtained for the two centres where it was available. These estimates may be too low, as enzyme immunoassay can fail to detect up to 10% of rotavirus-positive specimens.15 Conversely, they might be too high on a population-wide basis, as they were based on tertiary referral centres where the severity of admitted cases -- and therefore the likelihood of rotavirus involvement -- might be higher (although this was only weakly supported by our data on mean length of stay [LOS], which showed a small difference between RCH [mean LOS 1995-1996, 2.15 days] and the whole of Victoria [1.87 days], and no difference between PMH and WA averages [2.80 v. 2.85]). Our second method, based on a regression model, was subject to statistical fluctuations and assumptions that imply it might produce an underestimate of the rotavirus fraction (see Box name="box2"2). In particular, the coverage of rotavirus specimen collection varied between States and also, at times, within States. For example, only a relatively small number of specimens (457) were ascertained from New South Wales, implying that the rotavirus fraction for that State might be considerably underestimated. In fact, when the regression method was applied to the pooled national data, we found reasonable convergence between the two methods, and believe they both support the conclusion that 50% of all gastroenteritis admissions in this age group are due to rotavirus. A reasonable range of possible alternative estimates around this value would be from 40% to 60%. In other studies, estimates of the proportion of hospital admissions in children under five years attributable to rotavirus have ranged from around 30% to as high as 66%.3,4,6,8,9,16 United States studies from the Centers for Disease Control have estimated this proportion both by a simple "residual" method based on assuming that all diarrhoea admissions in the winter seasonal peaks are rotavirus-related,17 and a more direct method based on an eight-year series of children admitted to a Washington DC hospital.6 Both methods indicated that rotavirus was responsible for about one-third of admissions, and the corresponding annual rate of hospitalisation for rotavirus-related gastroenteritis in children under five years was 2.8 per 1000. In the United Kingdom, estimates have been based on laboratory surveillance and hospital discharge data, with a similar statistically based estimation procedure to ours.4 It was found that 43% of admissions in children under five years could be attributed to rotavirus, corresponding to 5.3 per 1000 admissions per year. A New South Wales study by Ferson also used a regression method, based on a larger sample of rotavirus surveillance data than ours, and estimated an annual rate of hospital admission of 8.7 per 1000.5 Using the 1993-1996 NSW hospital admission rates (Box name="box3"3), this corresponds to a rotavirus fraction of 51%, very consistent with our national estimate. Ferson's study found over twice the rate of rotavirus gastroenteritis in the second year of life compared with the first, a slightly greater difference than suggested by our data. The findings of both studies are consistent with a detailed investigation of children with gastroenteritis over 13 years at RCH Melbourne, which found that no pathogen could be identified in a substantially greater proportion of infants under six months than in older children.18 There were substantial differences in hospital admission rates between the States, with NSW, Queensland and South Australia having almost twice the rate of hospitalisation of Victoria. It seems very unlikely that these differences are the result of different disease patterns, especially as the seasonal patterns in these States were very similar. Nor are they likely to be explained by differences in coding, as our incidence figures are based on an inclusive selection of principal diagnosis ICD-9-CM codes. In particular, the inclusion of code 558.9 ("non-infectious gastroenteritis") identified a substantial number of apparently miscoded cases of viral diarrhoea, consistent with findings in other reports.4,5 The differences may reflect variations in patterns of primary care influencing the numbers of children who present to hospital emergency departments, and/or differences in hospital admission policies. The relative importance of each of these factors warrants further study, as it appears likely that substantial savings could be made if hospitalisation rates nationally could be reduced. There were no major seasonal differences in gastroenteritis incidence between States, except in the Northern Territory and Western Australia, where the relative importance of rotavirus in the gastroenteritis disease burden may be somewhat reduced. There is little evidence in our data of a progressive spread of the rotavirus epidemic across the country each year, in the manner that has been described in North America,19 apart from the fact that the annual peak of rotavirus activity in Western Australia appears generally to precede that in the eastern States. The Northern Territory was the most clearly distinct of all the regions, not only in its substantially higher hospital admission rate and lack of seasonal pattern, but also in the dramatically longer length of stay of patients. Average length of stay in this study (2.2 days, excluding the Northern Territory) was substantially shorter than that reported in the United States (3.9 days20), but very similar to British findings.4 Given the higher admission rates in Australia, shorter length of stay may reflect a less severe spectrum of illness, or possibly better management involving more widespread use of oral rehydration solution. Our results imply that 10 000 hospital admissions occur annually in Australia for rotavirus gastroenteritis. The direct cost of this hospital care is at least $12 million, based on an (Australian national diagnosis-related group-based) estimate of $1244 per admission,21 and may be as high as $15-$18 million (preliminary analysis, RCH [Melbourne] costing data). A successful rotavirus vaccine -- depending on its cost -- could result in substantial savings to the healthcare system. Acknowledgments The study was funded by the Public Health Research and Development Committee of the National Health and Medical Research Council. It would not have been possible without the generous cooperation of numerous individuals in all State and Territory health authorities, and in medical records and hospital information units at the participating hospitals, or without the participation and skilled assistance of the following microbiologists and paediatricians: G Davidson, P Goldwater, T Kok, A Lawrence, L Micken, S Weir (Adelaide); G Clift, J Erlich, J Hagger, R Matters, F Morey (Alice Springs); J Faogali, J Farrah, R Shepherd, M Witt (Brisbane); G Lum, A Lowe, A Ruben, B Way, K Withnall (Darwin); A Carmichael, A Claridge, K Dahlenburg, R Fang, R Tucker (Hobart); B Crawford, G Hogg, B Ross, R Schnagl, P Ward (Melbourne); B Dwyer, R Hill, A May, G O Connor, B Wild (Perth); P Amin, T Borg, A Cunningham, J MacRae, P McIntyre, C McIvor, K McPhie, J Mitchell, J Montgomery, G Sandico (Sydney). References Bishop RF, Davidson GP, Holmes IH, Ruck BJ. Virus particles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis. Lancet 1973; 2: 1281-1283. Bern C, Glass RI. Impact of diarrheal diseases worldwide. In: Kapikian AZ, editor. Viral infections of the gastrointestinal tract. New York: Marcel Dekker, 1994: 1-26. Glass RI, Kilgore PE, Holman RC, et al. The epidemiology of rotavirus diarrhea in the United States: surveillance and estimates of disease burden. J Infect Dis 1996; 174 (Suppl 1): S5-S11. Ryan MJ, Ramsay M, Brown D, et al. Hospital admissions attributable to rotavirus infection in England and Wales. J Infect Dis 1996; 174 (Suppl 1): S12-S18. Ferson MJ. Hospitalisations for rotavirus gastroenteritis among children under five years of age in New South Wales. Med J Aust 1996; 164: 273-277. Brandt CD, Kim HW, Rodriguez WJ, et al. Pediatric viral gastroenteritis during eight years of study. J Clin Microbiol 1983; 18: 71-78. Matson DO, Estes MK. Impact of rotavirus infection at a large pediatric hospital. J Infect Dis 1990; 162: 598-604. Konno T, Suzuki H, Imai A, et al. A long-term survey of rotavirus infection in Japanese children with acute gastroenteritis. J Infect Dis 1978; 138: 569-576. Spence L, Singer O, Kibsey P, Fauvel M. Rotavirus infection in children with diarrhoea admitted to a general hospital in metro Toronto. Can J Pub Health 1985; 76: 17-20. Lewis HM, Parry JV, Davies HA, et al. A year's experience of the rotavirus syndrome and its association with respiratory illness. Arch Dis Child 1979; 54: 339-346. Liddle JLM, Burgess MA, Gilbert GL, et al. Rotavirus gastroenteritis: impact on young children, their families and the health care system. Med J Aust 1997; 167: 304-307. Smith JC, Haddix AC, Teutsch SM, Glass RI. Cost-effectiveness analysis of a rotavirus immunization program for the United States. Pediatrics 1995; 96: 609-615. Barnes GL, Lund JS, Adams L, et al. Phase 1 trial of a candidate rotavirus vaccine (RV3) derived from a human neonate. J Paediatr Child Health 1997; 33: 300-304. Coulson BS, Unicomb LE, Pitson GA, Bishop RF. Simple and specific enzyme immunoassay using monoclonal antibodies for serotyping human rotaviruses. J Clin Microbiol 1987; 25: 509-515. Husain M, Seth P, Broor S. Detection of group A rotavirus by reverse transcriptase and polymerase chain reaction in feces from children with acute gastroenteritis. Arch Virol 1995; 140: 1225-1233. Donelli G, Ruggeri FM, Tinari A, et al. A three-year diagnostic and epidemiological study on viral infantile diarrhoea in Rome. Epidemiol Infect 1988; 100: 311-320. Ho MS, Glass RI, Pinsky PF, Anderson LJ. Rotavirus as a cause of diarrheal morbidity and mortality in the United States. J Infect Dis 1988; 158: 1112-1116. Barnes GL, Uren E, Stevens KB, Bishop RF. Etiology of acute gastroenteritis in hospitalized children in Melbourne, Australia, from April 1980 to March 1993. J Clin Microbiol 1998; 36: 133-138. LeBaron CW, Lew J, Glass RI, et al. Annual rotavirus epidemic patterns in North America: Results of a 5-year retrospective survey of 88 centers in Canada, Mexico, and the United States. JAMA 1990; 264: 983-988. Jin S, Kilgore PE, Holman RC, et al. Trends in hospitalizations for diarrhea in United States children from 1979 through 1992: estimates of the morbidity associated with rotavirus. Pediatr Infect Dis J 1996; 15: 397-404. Australian casemix report: on hospital activity, 1995-96. Canberra: Department of Health and Family Services, 1997. (Received 30 Oct 1997, accepted 4 May 1998) Authors' details Clinical Epidemiology and Biostatistics Unit, Royal Children's Hospital, Melbourne, VIC. John B Carlin, BSc(Hons), PhD, Deputy Head, and Associate Professor, Department of Paediatrics, University of Melbourne; Patty Chondros, BSc(Hons), Research Assistant. Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Melbourne, VIC. Paul Masendycz, BAppSc, Research Assistant; Helen Bugg, BSc, Research Assistant; Ruth F Bishop, AO, DSc, PhD, Senior Principal Research Fellow (NHMRC, and Professor, Department of Paediatrics, University of Melbourne; Graeme L Barnes, MD, FRACP, Senior Gastroenterologist, and Associate Professor, Department of Paediatrics, University of Melbourne. Reprints: Associate Professor G L Barnes, Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Parkville, VIC 3052. E-mail: barnesgATcryptic.rch.unimelb.edu.au - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

John B Carlin · Patty Chondros · Paul Masendycz · Helen Bugg · Ruth F Bishop · Graeme L Barnes

Screening for colorectal cancer: too early to be dogmatic The emotive, ethical and economic issues raised by population screening programs remain a challenge ©MJA1996; 165: 68-69 Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Support for screening for colorectal cancer in Australia has been gradually brewing, with reports in the national and international literature, 1-3 and evidence suggesting that colorectal cancer is increasing in prevalence. Despite improvements in surgical technique and adjuvant therapies, overall survival in the symptomatic phase of the disease has remained static. Now a well performed, randomised controlled trial of repetitive faecal occult blood testing has shown, for the first time, a small survival benefit from screening, 1 and evidence from case-control studies suggests that flexible sigmoidoscopy screening may have an even greater mortality benefit. 2,3 In this issue of the Journal, two articles -- a review of screening for colorectal cancer by Macrae ( page 102 ), and a pilot study of flexible sigmoidoscopy screening for colo rectal cancer by Olynyk et al. ( page 74 ) -- highlight this renewed interest in screening for colorectal cancer. Clinical epidemiology and the assessment of screening have evolved into a science, with epidemiologists, clinicians and statisticians collaborating in government working parties throughout the world to assess preventive practices for cancers. 4 In 1996 the momentum for screening prompted an Australian Health Technology Advisory Committee Working Party on colorectal cancer screening to try to sort out the evidence for and against screening, and to establish guidelines for national programs. This is no small task. MEDLINE alone detects over 800 relevant publications on bowel cancer screening, and, as computer searches miss more than 50% of randomised controlled trials, there is obviously a vast ocean of written "evidence" to be found and assessed. 5 Despite reviewing the same body of evidence, collaborating on initial interpretations and adopting a scientific approach to the assessment of screening for colorectal cancer, the Task Forces of Canada and the United States have made different recommendations. 6,7 A stepwise approach to assessing colorectal cancer screening identifies the point in the assessment where the two bodies disagree and the Australian Working Party must adjudicate for the Australian population (Box). 4 The major differences relate to the interpretation of one randomised controlled trial of faecal occult blood testing and two case-control studies of flexible sigmoidoscopy, although the much-awaited results of two further randomised controlled trials of faecal occult blood testing should be available in the near future. 1-3 There is agreement that the Minnesota trial 3 has shown a statistically significant cancer-specific mortality benefit and that this equates to 2.95 lives saved per 1000 people repetitively screened annually with faecal occult blood testing for 13 years. A 10% false positive rate and the 86% quoted compliance would mean an estimated colonoscopy procedural cost alone of over $100 000 per life saved after 13 years in Australia. The United States and Canadian Task Forces have agreed on the efficacy, effectiveness and efficiency of the data (Steps 1-3), but differ in their assessment of the small but expensive cancer-specific mortality benefit of faecal occult blood testing and the allocation of limited resources (Step 4). Interpretation of case-control studies for flexible sigmoid o scopy has remained at the proof-of-efficacy stage (Step 1). Does an 18% difference in rates of flexible sigmoidoscopy for those who died from colorectal cancer equate to a survival benefit in the control subjects who have not died from this disease? 2 The alternative hypothesis is that this difference is due to selection bias inherent in this retrospective study design. 7 The lack of detection of any colorectal cancer in the control group, and the detection of adenoma in only 1% of control subjects, imply no mortality benefit from their 24% sigmoidoscopy rate. 2 True mortality benefit would have to come from an intervention that detected early cancers or high risk adenomas and resulted in successful treatment. This would suggest that the cases and controls are not comparable and that a randomised controlled trial is still required to answer this question. The Fremantle pilot project reported by Olynyk et al. ( page 74 ) detected colorectal cancer at their estimated cost of $500 per screened patient (unpublished data). Thus, the true cost of detecting a cancer with flexible sigmoidoscopy in Australia may be $85 000, with no evidence as yet of a mortality benefit. The same data can and will be interpreted differently by different authors, health departments, societies and foundations. To some extent screening can be supported by the current data, but dogmatic conclusions and recommendations remain controversial and raise issues for discussion. Currently, these revolve around the statistical versus clinical significance of the small cancer-specific mortality benefit of annual faecal occult blood screening; the lack of detection of any cancers or significant polyps in the control groups of case-control studies of flexible sigmoidoscopy to explain any mortality benefit from sigmoidoscopy; and the lack of compliance with many of the screening programs. There is also a lack of research into the potential adverse effects of national screening programs, such as physical complications and problems arising from labelling or mis labelling of people screened (which may have psychological effects and also life and medical insurance repercussions). Even the earlier detection of incurable disease may have adverse effects. 4 The general population's desire for cancer screening may not be as great as that of its advocates; non-compliance would then impact upon efficacy. There is little doubt the emotive and ethical issues raised by population screening programs will challenge us for many years to come. Costs need to be compared with number of lives saved, and screening programs balanced against other programs competing for the limited available health care resources. Programs are often promoted by interested parties with more rhetoric than scientific evidence. The exciting advances of recent years -- that colorectal cancer can be detected and treated in the asymptomatic phase with improvement in mortality -- have encouraged clinical researchers, but the best means of achieving this has yet to be established. It may be that the advances and ethical quandaries of genetic testing hold the key to the future and will be the focus of this debate. Michael J Solomon Colorectal Surgeon Director of Research, University of Sydney, and Central Sydney Departments of Colorectal Surgery, Sydney, NSW Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for faecal occult blood. N Engl J Med 1993; 328: 1365-1371. Selby JV, Friedman GD, Quesenberry CP, Weiss NS. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992; 326: 653-657. Newcomb PA, Norfleet RG, Stoner BE, et al. Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 1992; 84: 1572-1575. Hunt J, Solomon MJ. Screening for cancer: the science behind the rhetoric. Int J Surg Sci 1995; 2: 161-167. Solomon MJ, McLeod RS, Laxamana A, Devore L. Randomized controlled trials in surgery. Surgery 1994; 115: 707-712. US Preventive Sevices Task Force. Guide to clinical preventive services. 2nd ed. Baltimore : Williams & Wilkins, 1996: 89-104. Solomon MJ, McLeod RS and the Canadian Task Force on the Periodic Health Examination. Periodic Health Examination, 1994 update: 2. Screening strategies for colorectal cancer. Can Med Assoc J 1994; 150: 1961-1970. - Register to be notified of new articles by email - - To top of article - ©MJA; 1996 < URL: http://www.mja.com.au/> © 1996 Medical Journal of Australia.

Michael J Solomon

Flexible sigmoidoscopy screening for colorectal cancer in average-risk subjects: a community-based pilot project John K Olynyk, Sina Aquilia, David R Fletcher and Jim A Dickinson ©MJA1996; 165: 74-76. This article has been cited in Sladden MJ, Ward JE. Australian general practitioners' views and use of colorectal cancer screening tests. MJA 1999; 170: 110-113 Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Abstract - Introduction - Methods - Subjects - Data management - Acceptability survey - Results - Subject recruitment - Screening results - Reasons for non-compliance with screening - Discussion - Acknowledgements - References - Author's Details - Register to be notified of new articles by email - - To top of article - ©MJA; 1996 Abstract Objective: To test a pilot screening program for colorectal cancer. Design: Subjects, chosen at random and recruited by mail, were examined by flexible sigmoidoscopy. Participants and setting: Normal-risk, asymptomatic men and women aged 55-59 years recruited from the community, July to December, 1995. Main outcome measures: Number of polyps detected and cancers diagnosed, and compliance with screening. Results: Letters of invitation were sent to 3500 subjects; of these, 2881 were eligible for inclusion in the study and 342 (12%) consented to participate. A further 3.5% of non-compliant subjects attended the screening program after a telephone survey assessing reasons for non-attendance. Common reasons for non-attendance were a lack of interest (30%) or a lack of time, mainly due to work commitments (28%). A third of subjects had polyps and 46% of these were adenomas. Three subjects were found to have adenocarcinoma: in two the cancer was confined to a polyp and treated with polypectomy, and one subject underwent anterior resection (overall prevalence of cancer, 0.9%). The median depth of insertion achieved with flexible sigmoidoscopy was 55 cm (range, 25-100 cm). Median pain level (on a scale of 0 = no pain to 10 = worst pain imaginable) was 2 (range, 0-8.5), and 99% of the subjects would have the test again if required. Conclusions: Flexible sigmoidoscopy was well tolerated and had an acceptable detection rate of adenomatous polyps and early cancer. Subject compliance emerged as a major issue which requires further evaluation to maximise participation in future programs. MJA 1996; 165: 74-76 Introduction C olorectal cancer is the commonest cancer affecting both sexes and isnow the second-commonest cause of cancer-related death in both men and women. 1 Several studies have shown that screening asymptomatic populations may reduce mortality from colon cancer by up to 30%, 2-4 and recently the World Health Organization recommended screening of asymptomatic subjects beginning at age 50. 5 However, in Australia there are no uniformly agreed methods for screening asymptomatic subjects for colorectal cancer. 6 Factors such as screening efficacy, cost, subject compliance and strategies employed to evaluate positive results all influence the choice of screening test. Faecal occult blood testing for colo rectal cancer is relatively cheap, but is limited by a high rate of false positive results and poor sensitivity. 7-9 A recent report also suggests that up to half the mortality reduction observed with faecal occult blood screening may be due to chance selection for colonoscopy. 10 Flexible sigmoidoscopy has been proposed as an alternative screening test. It is more expensive but would prevent more cancer deaths than faecal occult blood testing alone. 8,11 Apart from determining the best screening methods, rates of compliance with screening programs range widely (8%-80%). 8,12 These issues, together with implications for health service resource allocation, have prompted recommendations for pilot programs to determine the efficacy of screening and compliance rates before more generalised screening is introduced. 6,8,13 The Western Australian Department of Health provided funds for such a pilot project at Fremantle Hospital. Thus, we were able to conduct a pilot community-based flexible sigmoid oscopy screening program, between July and December 1995, for colorectal cancer in normal-risk asymptomatic individuals, and in this setting determine (i) yield of screening, and (ii) subject compliance with screening and factors which influence compliance. Methods A flexible sigmoidoscopy facility dedicated to colorectal cancer screening was established at Fremantle Hospital. All procedures were performed on an outpatient basis after informed written consent. No sedation was used. After administration of a phosphate enema, procedures were performed either by a qualified gastroenterologist, or a general practitioner who was undergoing supervised training in flexible sigmoidoscopy. An Olympus TI100 colonoscope (Olympus Optical, Japan) was used, allowing insertion up to 100 cm. Biopsies were taken from polyps seen during the procedure. Subjects with biopsy-proven adenomas were advised to have a follow-up colonoscopy. A computer-generated report was issued to all subjects after the procedure, with instructions to return to their general practitioner for ongoing care. The study was approved by the Ethics Committee of Fremantle Hospital. Subjects We recruited male and female subjects aged 55 to 59 years of age using a computerised database derived from the Western Australian Electoral Commission. Letters were sent to 3500 randomly selected subjects inviting their participation. Exclusion criteria (apart from age less than 55 or greater than 59 years) were: symptoms of recent alteration in bowel habit, constipation, diarrhoea, or passage of blood with bowel motions; previous history of colonic polyps or colorectal cancer; and family history of colorectal cancer. A telephone survey of 200 subjects who did not respond to the initial letter showed that the reason for non-attendance in 14% of these subjects was that they met the exclusion criteria. Data management All data were recorded on a customised database from which reports were generated. We recorded basic demographic data, presence or absence of exclusion criteria, operator information, date of procedure, adequacy of bowel preparation, insertion depth, polyp data (number, size, pedunculated or sessile, biopsy report and date), and follow-up advice. Acceptability survey After the procedure, 77 consecutive subjects filled in a brief questionnaire, which included a standard 10-cm linear analogue pain scale. They marked a 10-cm line (labelled "0 = no pain" and "10 = worst pain imaginable") at a point which corresponded to their level of pain. Results Subject recruitment One hundred and fifty letters were returned, indicating that the subject was no longer resident at the mailing address. As 14% of non-attending subjects were found by the telephone survey to meet exclusion criteria, we estimate there were 2881 eligible subjects. Of those, 342 (12%) consented to participate in the study. There were 200 men and 142 women participants; 95% were born in Australia. Screening results Findings at flexible sigmoidoscopy are summarised in Box 1. The median depth of insertion achieved was 55 cm (range, 25-100 cm; 70% of subjects had at least 50 cm of bowel examined by flexible sigmoidoscopy. Thirty-five subjects (10%) were incompletely prepared with one enema and required a repeat bowel preparation before the procedure. Thirty-five per cent of subjects had polyps -- 46% of these polyps were adenomas, the remainder being hyperplastic or metaplastic polyps. The median adenoma size was 4 mm (range, 1-60 mm). Nineteen of the adenomatous polyps (5.6%) were at least 1 cm in size. One subject with a 6-cm sessile villous adenoma underwent anterior resection. Three subjects were found to have adenocarcinoma -- in two the cancer was confined to a polyp and treated with polypectomy, while the third required anterior resection for a cancer detected at follow-up colonoscopy. The overall prevalence of cancer in this group of subjects was 0.9%. The median pain score attributed to the procedure was 2 (range, 0-8.5). Seventy-six (99%) of these subjects would have the test again if required. Most subjects found the procedure interesting (they were able to watch on a video screen) and worthwhile. Reasons for non-compliance with screening The commonest reasons given for non-compliance were a lack of interest (30%) or a lack of time, mainly due to work commitments (28%) (Box 2). Interestingly, 16% of subjects who did not attend stated that they had either discussed the issue of bowel cancer screening to their satisfaction with their local general practitioner or had been screened for bowel cancer. Seventeen (8%) of the 200 subjects who did not attend as a result of the initial mail-out indicated that they would like to participate as a direct result of the telephone interview and were offered appointments; seven (3.5%) of these subjects have since attended for screening. Discussion The cancers detected by flexible sigmoidoscopy in our study were early cancers, but our three cases represent a detection rate of 8.8 cancers per 1000 asymptomatic subjects aged 55-59. Western Australian data for this age group predict an annual incidence of about 1 per 1000. 1 Our yield of polyps at least 1 cm in size (5.6%) is consistent with the previously reported prevalence of polyps in persons aged 55-59 14 and in asymptomatic Australian men of mean age 66 (3.8%). 15 However, the depth of insertion and number of polyps found in our study are both greater than those reported in several recent studies of flexible sigmoidoscopy: their average depth of insertion ranged from 30 to 50 cm 16-19 and polyp yield ranged from 1% to 4%. 18,19 There is little doubt that population response to screening will be a major determinant of the utility of flexible sigmoidoscopy as a screening tool for colo rectal cancer. The reasons given for non-compliance are similar to those reported for non-attendance in faecal occult blood screening programs. 20 Although the initial response in the pilot program was 12%, the survey of non-compliant subjects demonstrated a significant opportunity for improvement. An additional 3.5% of subjects could immediately be given an appointment at the time of the telephone survey of non-compliant subjects, bringing the compliance rate to 15.5%. Of the remaining reasons determined for non-compliance, most could be addressed by better education of subjects, and rescheduling of screening times to suit the work practices of potential candidates. It remains to be seen how much this would actually improve screening rates. Sixteen per cent of non-compliant subjects reported that they had either been screened for colorectal cancer or had discussed the issue to their satisfaction with their local general practitioner. This may reflect the growing public and general practitioner awareness of colon cancer screening; this has recently been reported from South Australia. 21 There is no doubt that the highest possible compliance should be aimed for, but in a society where currently only 41% of subjects with rectal bleeding seek medical attention 22 it would seem that much education needs to occur to facilitate this process. We have reported the first Australian pilot study of flexible sigmoidoscopy screening of asymptomatic subjects aged 55-59 years in which a high yield of adenomatous polyps and early cancers was found. The procedure was well tolerated. Subject compliance emerged as a major issue which requires further evaluation in order to maximise participation in future programs. This study strongly supports a more broad-scale evaluation of flexible sigmoidoscopy screening of asymptomatic subjects for colorectal cancer and polyps. Acknowledgements We wish to thank Dr Digby Cullen, Mr Graham Cullingford and the Gastroenterology Departments of Fremantle Hospital, Sir Charles Gairdner Hospital and Royal Perth Hospital; Dr Andrew Penman, formerly Chief Health Officer of the Health Department of Western Australia, and the Fremantle Division of General Practice, for their support of this study. References Dobson SK, Penman AG, and 82 others. Clinical health goals and targets for Western Australia, Vol. 2. First report of the Western Australian Task Force on State Health Goals and Targets. Perth: Health Department of Western Australia, July 1994. Mandel JS, Bond JH, Church TH, et al. Reducing mortality from colorectal cancer by screening for faecal occult blood. N Engl J Med 1993; 328: 1365-1371. Selby JV, Friedman GD, Quesenberry CP Jr, et al. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992; 326: 653-657 . Newcomb PA, Norfleet RG, Storer BE, et al. Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 1992; 84: 1572-1575. Winawer SJ, St John DJ, Bond JH, et al. Prevention of colorectal cancer: guidelines based on new data. Bull World Health Organ 1995; 73: 7-10. Goulston K, St John J, Bokey L, et al. Guidelines for early detection, screening and surveillance for colo rectal cancer. 2nd edition. Sydney: Australian Gastroenterology Institute and Gastroenterological Society of Australia, 1994. Austoker J. Screening for colorectal cancer. BMJ 1994; 309: 382-386. Lieberman D. Screening/early detection model for colorectal cancer. Cancer 1994; 74: 2023-2027. Solomon MJ, McLeod RS and Canadian task force on periodic health examination. Can Med Assoc J 1994; 150: 1961-1970. Lang CA, Ransohoff DF. Faecal occult blood screening for colorectal cancer: is mortality reduced by chance selection for screening colonoscopy? JAMA 1994; 271: 1011-1013. Lieberman DA. Cost-effectiveness model for colon cancer screening. Gastroenterology 1995; 109: 1781-1790. Blalock SJ, De-Vellis BM, Sandler RS. Participation in faecal occult blood screening: a critical review. Prev Med 1987; 16: 9-18. St John J. Screening for colorectal cancer: "On your marks. . ." Med J Aust 1994; 160: 596-597. Arminski TC, McLean DW. Incidence and distribution of adenomatous polyps of the colon and rectum based on 1000 autopsy examinations. Dis Col Rectum 1964; 7: 249-261. Chapuis PH, Goulston KJ, Dent OF, Tait AD. Predictive value of rectal bleeding in screening for rectal and sigmoid polyps. BMJ 1985; 290: 1546-1548. Krevsky B, Fisher RS. Yield of rescreening for colonic polyps using flexible sigmoidoscopy. Am J Gastroenterol 1994; 89: 1165-1168. Maule WF. Screening for colorectal cancer by nurse endoscopists. N Engl J Med 1994; 330: 183-187. Renneker M, Saner H. Low-cost flexible sigmoid oscopy screening: a community demonstration and education project. J Cancer Educ 1995; 10: 25-30. Sakamoto MS, Hara JH, Schlumpberger JM. Screening flexible sigmoidoscopy in a low-risk, highly screened population. J Fam Pract 1994; 38: 245-248. Lindholm E, Berglund B, Haglind E, et al. Factors associated with participation in screening for colorectal cancer with faecal occult blood testing. Scand J Gastroenterol 1995; 30: 171-176. Weller D, Hiller J, Beilby J, et al. Screening for colorectal cancer: knowledge, attitudes and practices o f South Australian GPs. Med J Aust 1994; 160: 620-624. Crossland A, Jones R. Rectal bleeding: prevalence and consultation behaviour. BMJ 1995; 311: 486-488. (Received 6 Feb, accepted 22 Apr 1996) For editorial comment, see Solomon, page 68; see also Macrae, page 102. Authors' details University Department of Medicine and Department of Gastroenterology, Fremantle Hospital, Fremantle, WA. John K Olynyk , FRACP, MD, Senior Lecturer and Head of Department of Gastroenterology. Sina Aquilia , BA(Psych), Research Assistant. University Department of Surgery and Department of Gastroenterology, Fremantle Hospital, Fremantle, WA. David R Fletcher , FRACS, MD, Professor of Surgery, Head of Department of Surgery. University Department of General Practice, Fremantle Hospital, Fremantle, WA. Jim A Dickinson , FRACGP, PhD, Professor of General Practice. Reprints: Dr J Olynyk, University Department of Medicine, Fremantle Hospital, PO Box 480, Fremantle, WA 6160. E-mail: jolynyk AT uniwa.uwa.edu.au < URL: http://www.mja.com.au/> © 1996 Medical Journal of Australia.

John K Olynyk · Sina Aquilia · David R Fletcher · Jim A Dickinson

Screening for colorectal cancer, 1996 Finlay A Macrae Readers may print a single copy for personal use. No further reproduction or distribution of the articles in whole or in part should proceed without the permission of the publisher. For copyright permission, contact the Australasian Medical Publishing Company Screening average-risk people aged 55 to 70 years for colorectal cancer is now a public health priority in Australia. Pilot studies of faecal occult blood testing are required to find ways of achieving optimal compliance and cost efficiency in the Australian health care setting. Flexible sigmoidoscopy probably should be used as complementary screening but further trials are needed. High-risk groups (family history of colorectal cancer, or previous ulcerative colitis, adenomas or cancer) should already be in surveillance programs. (MJA 1996; 165: 102-105) Introduction - Average risk screening - Above average risk - Conclusion - References - Author's Details - Table 1 - Table 2 - Table 3 Introduction A convergence of events has placed colorectal cancer in the forefront of Australian public health policy formulation. Strategies to control the other major cancers (of the lung, breast and cervix) are now well developed, making it logical that colorectal cancer, as the commonest internal malignancy in Australia, 1 should now receive more attention. At the same time, techniques to detect colorectal cancer at an early (curable) stage have been refined, and large, long-term randomised studies to prove that these techniques can reduce mortality from colorectal cancer are nearing completion. 2-6 Our confidence in determining the outcome of these trials has increased with the development of rigorous methods to assess benefit. 7 Finally, the leading role that colorectal cell and molecular biology has taken in the science of carcinogenesis 8 means that delivery of molecular biological diagnostic services for cancer should already be a clinical service, at least for familial adenomatous polyposis and some other familial colo rectal cancers. Given the state of our knowledge, what should be done now about colorectal screening? Average risk screening Faecal occult blood testing The best chance of cure in colorectal cancer is surgical treatment when the disease is localised to the bowel wall (Australian Clinicopathological Staging System A [ACPS A]) or at least does not involve lymph nodes if it has penetrated through the muscle wall (ACPS B). This means the best chance of diagnosis is before symptoms develop. The most logical method of diagnosis is population screening to identify people with early-stage or premalignant (adenomatous polyps) tumours, but it is very difficult to prove that this will reduce mortality rate. Such proof is required to attract scarce health dollars. Rigorous controlled trials are needed to counter possible biases (e.g., lead-time bias: screening allowing an earlier diagnosis but not altering date of death or the tumour's natural history; and length bias: screening selecting biologically favourable tumours, such as slow-growing ones) and the requirement to analyse on an intention-to-treat basis 9 means recruiting over 100 000 people to adequately test the screening hypothesis. Three large randomised controlled trials of faecal occult blood testing are in progress 4-6 and several have been completed (Table 1). 2,3 The most important completed trial is the Minnesota trial, involving 46 551 subjects studied over 13 years and randomly allocated to annual, biennial or no Hemoccult testing (SmithKline Diagnostics Inc, San Jose, Calif, USA). 2 The trial demonstrated a statistically significant 33% relative reduction in mortality from colorectal cancer in subjects having annual testing. This result has withstood close scrutiny by critics, including those who believed that most of the benefit was attributable to chance because of the low specificity of the rehydrated Hemoccult test used, leading to over 30% of the screened population having a colonoscopy. 10 If the benefit was merely serendipitous, then the chance of a single positive occult blood test versus multiple tests (six were done with each screen) should not be linearly related (which it was), and the odds ratio for tumours in individuals testing positive versus negative to the presence of faecal occult blood would not have reached such high levels, far outstripping almost all other known risk factors. Thus, the Minnesota study shows that faecal occult blood testing does select patients with significant colorectal tumours. The three incomplete European randomised controlled trials are also on track to show a mortality reduction. 4-6 Supporting data come from case-control studies of faecal occult blood testing (Table 2). 11-13 The screening histories of people dying from colorectal cancer (cases) are compared with those of control subjects without apparent disease. A deficit of screening in the cases implies protection to the controls by screening. However, rigorous standards need to be applied to case-control studies to counter the subtle biases, which may account for the generally more favourable levels of protection found when compared with the results of randomised controlled trials. 7 Cohort studies of screening for colo-rectal cancer are curiously missing from the literature. Large cohort studies of diet and other possible risk factors for colo-rectal cancer have been published, 14,15 but none have recorded incidence of prior screening in those in the prospective cohort developing cancer versus those not developing cancer. Screening information is not reported in these studies, which seems a valuable opportunity lost. Many of the biases confounding case-control studies would be overcome in a cohort study of screening. New immunochemical tests have already demonstrated improved sensitivity and specificity, which will enhance the cost effectiveness and efficacy of screening programs. 16 Despite a statistically significant mortality benefit, the absolute number of lives saved per 1000 persons screened for faecal occult blood is small (about three). 2 This, of course, is a corollary of well patient screening (most of the people being screened are both free of disease and have negative results). We need to conduct studies to define cost-efficient procedures for screening, using tests with low false positive rates, and targeting particular communities. Sigmoidoscopy Sigmoidoscopy is likely to be an important adjunct for detection of distal colorectal cancer, as faecal occult blood testing has low sensitivity for rectosigmoid cancers. 17 Case-control studies of sigmoidoscopy screening show protection to the control groups (Table 2), 18,19 but it is difficult to identify the reason for the mortality benefit in terms of polyps removed or successful surgery for cancers detected at an early stage. Well accepted randomised controlled trials have not been done. Flexible sigmoidoscopy should detect 50%-70% of colorectal cancers, so its impact in screened populations is likely to be high. Indications from case-control studies are that protection lasts for 10 years, which augurs well for cost-benefit considerations. 18 Large randomised controlled trials of flexible sigmoidoscopy screening are commencing in Europe. 20 Colonoscopy Even once-off colonoscopy is comparable in cost with breast cancer screening. However, as with flexible sigmoidoscopy, colonoscopy screening does not have enough clinical research proof to be sure of its benefit, although this is probably just a matter of time. 21 Compliance in Australian populations at average risk is unknown. From clinical science to clinical service In summary, faecal occult blood testing is the screening method with the stongest data for deployment. But, should we wait for the results of the additional European controlled trials of screening, or act now on the evidence from the Minnesota trial and other published information? Despite its low sensitivity (about 50% for asymptomatic cancers), 4,21 repetitive screening programs have shown a reduction in mortality from colorectal cancer. Testing is cheap and simple and reasonably well accepted in Australian populations. 22 Provided specificity is high (and thus false positive results low), follow-up colonoscopy is both feasible and cost-manageable. 23 Although the scientific basis for implementing faecal occult blood screening for those aged 50-75 years of age is compelling, the best way to do this in Australia is uncertain. Should it be through dedicated centres providing testing and evaluation, as with breast screening in Australia? Should it be through general practice? through a central electoral-roll-resourced organisation? through hospitals? or through State cancer foundations/councils? These logistical questions need to be answered by pilot trials. 24 Mechanisms to evaluate the results on a population basis must be built into whichever system is introduced. Germany has funded faecal occult blood mass screening for over a decade but has a poorly developed evaluation infrastructure, thus denying the world an important opportunity for assessment. Sigmoidoscopy needs further study before introduction, but sufficient evidence is available to offer sigmoidoscopy to average-risk people in the age group 50 to 75 years who are already in the health care system (case finding). Technical skills and facilities for flexible sigmoidoscopy are limited and their availability must be increased. Issues of cleaning and disinfection, environmental hazards of glutaraldehyde, technical and lesion-recognition training, manpower, support personnel, capital support for equipment for a "type C" (office-based) procedure, all complicate the widespread use of flexible sigmoidoscopy. However, the benefits of being able to examine 50%-70% of the tumour territory of the large bowel make the objective worthwhile. Above average risk Family history For individuals with a family history of colorectal cancer the appropriate recommendations are generally less controversial (Table 3). Many consistent studies demonstrate risks two- to sixfold higher in individuals with first degree relatives with colorectal cancer, the risk relating to the earliest age of onset in the family and the number of first degree relatives affected. 25,26 If there is only one affected first degree relative, age at onset of the cancer is important: if the relative was under 55 years, the risk is six times the average risk (the same as the risk for those with two first degree relatives with onset at any age); if a single affected relative has older-onset cancer, the increased risk to family members is marginal. 25 Thus, average-risk screening is recommended for those families with a single affected relative with older-age onset ( > > 55 years) of colorectal cancer (faecal occult blood testing and five-yearly flexible sigmoidoscopy), but colonoscopy every five years is recommended for those with a first degree relative with early-age onset. 24 If multiple family members are affected in a nuclear family, colonoscopy is recommended for first degree relatives of affected members, either five-yearly or three-yearly, depending on whether two or more relatives are affected. This advice is based on logical grounds of cost benefit: the higher the risk (and therefore prevalence) the greater the positive predictive value of screening, and thus cost-benefit. Protection may be enhanced by annual faecal occult blood testing between colonoscopies. The significance of a family member with an adenoma (as distinct from a cancer) is less clear in defining risks to individuals in the family. Epidemiological studies suggest that adenomas are equivalent to cancers, 27,28 but problems of detection bias make it difficult to use this information for surveillance advice. Nevertheless, a relative with a confirmed adenoma should not be ignored in assessing family history, and for risk assessment purposes it should be considered that these lesions may represent early cancer. Hereditary Non-Polyposis Colorectal Cancer syndrome is suspected when three or more first degree relatives have colorectal cancer (especially right-sided or multiple), with at least one affected family member < 50 years of age or when colo rectal cancer is associated with ovarian, endometrial, gastric, small-bowel, pancreatic, biliary, kidney or ureteric tumours. 29,30 Genotyping for these families is available in Australian research studies, but it may take over 12 months to define the family- specific mutation of the mismatch repair genes responsible. 31 Colonoscopy every two years for affected and at-risk family members is important, with faecal occult blood testing between colonoscopies. Familial adenomatous polyp-osis should also be suspected in families with early-age-onset colo-rectal cancer. Enquiry should be made about polyps or polyposis in affected members and confirmation of the diagnosis sought. Genotyping is available but is still technically difficult due to the large gene responsible ( APC gene); mutations at different sites in the gene are responsible for the condition in different families. 32 Once the mutation in a family is identified in genomic DNA, a family-specific DNA test is easily developed and available for predictive (100% accurate) testing in at-risk family members of any age. Expert genetic counselling is required. Issues of threats to insurance of all types, employment, survivor guilt, prognosis and family planning all need to be handled sensitively and informatively both before and after testing. Screening of APC- mutation carriers needs to proceed as before: annual or biennial flexible sigmoidoscopy screening from 15 to 55 years of age. Those without the mutation are recommended to have average risk screening. They are still at risk for common colorectal cancer. Previous adenomas or cancer: "polyp follow-up" Patients with previous adenomas or cancers face a similar risk for future cancer. 33-36 Although no randomised controlled trials have been reported, several large follow-up studies of patients with adenoma have compared outcomes with suitable control groups -- some with adenomas untreated, some with age-sex-matched population control groups, some with patients with polyps detected by barium enema (not removed) before colonoscopy was available -- and demonstrated a convincing reduction in mortality from regular follow-up. 34,35,37,38 The only exception is patients with small tubular adenoma(s) in the rectosigmoid region, where risk for subsequent cancer is no higher than average and surveillance is unlikely to be of particular value. 35 Intervals of surveillance are controversial but the United States National Polyp Study clearly demonstrated that annual follow-up conferred no benefit over three-yearly follow-up; 39 two- to five-yearly follow-up is recommended, depending on multiplicity, size of index adenoma and, possibly, family history -- all independent risk factors for subsequent neoplastic risk. Ulcerative colitis Ulcerative colitis poses a cancer risk after eight years for total disease and 12 years for left-sided disease. 40 The programs with best results advocate multiple biopsies (18 biopsies from eight colonic sites). Controlled trials have not been performed. 40 In summary, controlled trials of surveillance in these above average risk groups would confirm the recommendations but, on current knowledge, ethical considerations would not permit randomisation to no surveillance. Case-control and cohort studies in these above average risk groups providing information on benefit have not been published. Conclusion The prevalence of colorectal cancer in Australia, its surgical curability if detected at an early stage and recent controlled- trial evidence of mortality reduction by faecal occult blood screening now place colorectal cancer on the public health prevention agenda in Australia. The conservative and influential US Preventative Services Task Force has recently, for the first time, accepted the evidence for benefit as fair, and recommended screening for all persons aged 50 and over with faecal occult blood testing, or sigmoidoscopy, or both. 41 The Canadian Task Force on the Periodic Health Examination also accepts the evidence for mortality benefit, but raises concerns about costs driven by low sensitivity and specificity of the tests used in the Minnesota trial. 42 The optimal processes for implementing screening in a cost efficient manner using up-to-date screening tests require studies in pilot public health programs. Australia needs to move forward in this area, to help control its commonest internal cancer (that touches so many Australian families), and its second-largest cause of cancer mortality. References Coates M, McCredie M, Armstrong B. New South Wales Central Cancer Registry, Cancer in New South Wales, Annual reports 1973-1990. Incidence and mortality. Sydney: NSW Cancer Council, 1991. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. N Engl J Med 1993; 328: 1365-1371. Winawer SJ, Flehringer BJ, Schottenfeld D, Miller DG. Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 1993; 85: 1311-1318. Hardcastle JD, Thomas WM, Chamberlain J, et al. Randomised controlled trial of faecal occult blood screening for colorectal cancer: results of first 107 349 subjects. Lancet 1989; 1: 1160-1164. Kronborg O, Fenger C, Olsen J, et al. Repeated screening for colorectal cancer with faecal occult blood test: a prospective randomized study at Funen, Denmark. Scand J Gastroenterol 1989; 24: 599-606. Kewenter J, Bjork S, Haglind E, et al. Screening and re-screening for colorectal cancer. A controlled trial of fecal occult blood testing in 27 700 subjects. Cancer 1988; 62: 645-651. Gill TM, Horwitz RI. Evaluating the efficacy of cancer screening: clinical distinctions and case-control studies. J Clin Epidemiol 1995; 48: 281-292. Ee HC, Young JP. DNA repair and inherited cancer. J Gastroenterol Hepatol 1995; 10: 108-109. Newell D. Intention-to-treat analysis: implications for quantitative and qualitative research. Int J Epidemiol 1992; 21: 837-841. Lang CA, Ransohoff D. Fecal occult blood screening for colorectal cancer. JAMA 1994; 271: 1011-1013. Selby JV, Friedman GD, Quesenberry CP, Weiss NS. Effect of fecal occult blood testing on mortality from colorectal cancer. A case-control study. Ann Intern Med 1993; 118: 1-6. Wahrendorf J, Robra B-P, Wiebelt H, et al. Effectiveness of colorectal cancer screening: results from a population-based case-control evaluation in Saarland, Germany. Eur J Cancer Prev 1993; 2: 221-227. Saito H, Soma Y, Koeda J, et al. Reduction in risk of mortality from colorectal cancer by fecal occult blood screening with immunochemical hemagglutination test. A case-control study. Int J Cancer 1995; 61: 465-469. Willett W, Stampfer MJ, Colditz GA, et al. Relation of meat, fat and fiber intake to the risk of colon cancer in a prospective study in women. N Engl J Med 1990; 323: 1664-1672. Phillips RL, Snowdon DA. Dietary relationships with fatal colorectal cancer among Seventh-day Adventists. J Natl Cancer Inst 1985; 74: 307-317. St John DJB, Young GP, Alexeyeff MA, et al. Evaluation of new occult blood tests for detection of colorectal neoplasia. Gastroenterology 1993; 104: 1661-1668. Macrae FA, St John DJB. Relationship between patterns of bleeding and Hemoccult sensitivity in patients with colorectal cancers or adenomas. Gastroenterology 1982; 82: 891-898. Selby JV, Friedman GD, Quesenberry CP, Weiss NS. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992; 326: 653-657. Newcomb PA, Norfleet RG, Stoner BE, et al. Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 1992; 84: 1572-1575. Atkin WA, Cuzick J, Northover JMA, Whynes DK. Prevention of colorectal cancer by once-only sigmoidoscopy. Lancet 1993; 341: 736-740. Rex DK, Lehman GA, Hawes RH, et al. Screening colonoscopy in asymptomatic average risk persons with negative fecal occult blood tests. Gastroenterology 1991; 100: 64-67. Macrae FA, Hill I, St John DJB. Predicting colon cancer screening behaviour from health beliefs. Prev Med 1984; 13: 115-126. Frommer DJ, Kappario A, Brown MK. Improved screening for colorectal cancer by immunochemical detection of occult blood. BMJ 1988; 296: 1092-1094. Australian Gastroenterology Institute/Australian Cancer Society. Guidelines for early detection screening and surveillance for colorectal cancer, 2nd ed. Sydney: Australian Gastroenterology Institute/Australian Cancer Society, 1994. St John DJB, McDermott FT, Hopper JL, et al. Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 1993; 188: 785-790. Lovett E. Family studies in cancer of the colon and rectum. Br J Surg 1976; 63: 13-18. Maire P, Morichau-Beauchant M, Drucker J, et al. PrŽvalence familiale du cancer du c(tm)lon, et du rectum: rŽsultats d'une enqute "cas-tŽmoins" de 3 ans . Gastroenterol Clin Biol 1984; 8: 22-27. Winawer SJ, et al. Risk of cancer in relatives of patients with adenomas. N Engl J Med. In press. Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumour spectrum and pathology of hereditary non-polyposis colorectal cancer: an updated review. Gastroenterology 1993; 104: 1535-1549. Macrae FA. Bowel cancer: watching over the family. J Gastroenterol Hepatol 1995; 10: 337-338. Kohonen-Cornish M, St John DJB, Macrae FA, et al. Genetic defects in hereditary non-polyposis colon cancer. J Hepatol Gastroenterol 1995; 10: A38. Nagase H, Miyoshi Y, Horii A, et al. Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients. Cancer Res 1992; 52: 4055-4057. Grossman S, Milos ML, Tewaka IS, Jewell NP. Colonoscopic screening of persons with suspected risk factors for colon cancer. II. Past history of colorectal neoplasms. Gastroenterology 1989; 96: 299-306. Williams CB, Macrae FA. The St Mark's neoplastic polyp follow-up study. In: Rozen P, Winawer SJ, editors. Secondary prevention of colorectal cancer: An international perspective. Basel: Karger, 1986: 226-242. Atkin WS, Morsm BC, Cuzick J. Long-term risk of colorectal cancer after excision of rectosigmoid adenomas. N Engl J Med 1992; 326: 658-662. Bulow S, Svendsen LB, Mellemgaard A. Metachronous colorectal cancer. Br J Surg 1990; 77: 502-505. Winawer SJ, Zauber AG, et al. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 1993; 329: 1977-1981. Murakami R, Tsukuma H, Kanamori S, et al. Natural history of colorectal polyps and the effect of polypectomy on occurrence of subsequent cancer. Int J Cancer 1990; 46: 159-164. Winawer SJ, Zauber AG, O'Brien MJ, et al. Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. N Engl J Med 1993; 328: 901-906. Lennard Jones JE, Melville DM, Morson BC, et al. Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years. Gut 1990; 31: 800-806. US Preventive Services Task Force. Guide to clinical preventive services. 2nd ed. Baltimore: Williams & Wilkins, 1996: 89-103. Solomon MJ, McLeod RS and the Canadian Task Force on the Periodic Health Examination. Periodic health examination, 1994 update: 2. Screening strategies for colorectal cancer. Can Med Assoc J 1994; 150: 1961-1970. For editorial comment, see Solomon, page 68; see also Olynyk et al., page 74. Author's details Department of Gastroenterology, Royal Melbourne Hospital, Melbourne, VIC. Finlay A Macrae, MD, FRACP, Physician and Gastroenterologist. Reprints: Dr Finlay A Macrae, Department of Gastroenterology, The Royal Melbourne Hospital, PO Royal Melbourne Hospital, VIC 3050. To top of article - ©MJA; 1996 < URL: http://www.mja.com.au/> © 1996 Medical Journal of Australia.

Finlay A Macrae