Rapid Responses to:

PAPERS: Christopher E Macdonald, Anthony C Wicks, and Raymond J Playford Final results from 10 year cohort of patients undergoing surveillance for Barrett's oesophagus: observational study BMJ 2000; 321: 1252-1255 [Abstract] [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

Surveillance In Barretts Oesophagus

Roger Ferguson   (20 November 2000)

Studies on screening in Barrett's oesophagus must be relevent to modern practice

Ian Beales   (28 November 2000)

Hung jury on surveillance for Barrett's oesophagus: inadequate data

Rebecca C Fitzgerald   (30 November 2000)

Re: Hung jury on surveillance for Barrett's oesophagus: inadequate data

R J Playford   (4 December 2000)

Re: Studies on screening in Barrett's oesophagus must be relevent to modern practice

R J Playford   (4 December 2000)

Biomarkers to refine surveillance of Barrett's oesophagus patients

Christopher Wild   (9 January 2001)

surveillance endoscopy should never be discouraged

Helen Dresner   (3 February 2001)

Surveillance In Barretts Oesophagus 20 November 2000
Roger Ferguson, Consultant Gastroenterologist Wirral Hospital Send response to journal: Re: Surveillance In Barretts Oesophagus	This is a very reassuring paper for those of is in busy district general hospitals. I see a lot of patients with Barretts Oesophagus. There is no possible way that I can offer these patients a yearly endoscopy. My practice has been to offer younger patients (under 60 years), and those with complications 2 yearly endoscopy, taking 4 routine biopsies and biopsies from other areas that look "odd". I have yet to find a carcinoma that had not been suspected for clinical reasons. Yours sincerely Roger Ferguson
Studies on screening in Barrett's oesophagus must be relevent to modern practice 28 November 2000
Ian Beales, Consultant Gastroenterologist James Paget Healthcare NHS Trust, Lowestoft Road, Gorleston, NR31 6LA Send response to journal: Re: Studies on screening in Barrett's oesophagus must be relevent to modern practice	This paper will undoubtedly be quoted by those who feel that screening for oesophageal adenocarcinoma in groups at increased risk is a waste of effort and resources. However, the data contained within the paper by MacDonald et al do not add anything useful to the debate on the effectiveness of screening if modern surveillance programs are being discussed. The protocol used by MacDonald et al may have been that recommended and commonly performed at the initiation of their study but such a policy is inappropriate given current understanding of columnar-lined oesophagus and does not match modern recommendations. During the course of their study it was reported elsewhere that the it was the presence of specialized intestinal metaplasia in the oesophagus which was the risk factor for malignant transformation.(1,2) By performing surveillance on all patients with an endoscopically visible glandular oesophageal lining the authors enrolled not only those believed to be at risk of malignant transformation but those at no risk of malignant transformation (without specialized intestinal metaplasia). Thus many of the screening endoscopies were never going to detect malignant change and it is not surprising that the intensive annual endoscopy protocol had such a low yield overall. Streitz et al reported that screening endoscopies at a mean interval of 17 months, detected 1 cancer per 73 patient-year of follow up and overall was more cost effective that mammographic screening for breast cancer.(3) The most sensible current recommendations for screening in Barrett’s oesophagus are American, they suggest endoscopy at 2-3 year intervals in those with intestinal metaplasia (4) and thus the findings of MacDonald et al, although of historical interest do not provide useful data on which to discuss current practice. An additional point which deserves comment is the prominent and incorrect use of the term Barrett’s oesophagus. By placing this in the title, the authors have helped perpetuate the confusion surrounding the diagnosis. The authors’ use of the historical definition is at odds with the modern definition (a change in the appearance of the oesophageal mucosa recognizable at endoscopy with intestinal metaplasia on histology).(3,5) Therefore it can be seen that many of the patients in the study did not really ever have Barrett’s oesophagus. A quick discussion with my surgical and pathological colleagues confirmed that “Barrett’s oesophagus” means many different things to different people and by emphazing the incorrect use of the term MacDonald et al will have only exacerbated this. The term is so well established in the lexicon that it may be impossible to remove but it would be preferable if the more precise descriptive terms, columnar-lined oesophagus with or without specialized intestinal metaplasia and specialized intestinal metaplasia at the gastro- oesophageal junction were used in future.(5) Whilst I agree with MacDonald et al that screening policies for oesophageal adenocarcinoma require careful scrutiny for their effectiveness, it is important that the appropriate practice is studied. References 1 Reid BJ, Weinstein WM. Barrett's esophagus and adenocarcinoma. Annu Rev Med 1987;38:477-92:477-492. 2 Reid BJ. Barrett's esophagus and esophageal adenocarcinoma. Gastroenterol Clin North Am 1991;20:817-834. 3 Streitz JM, Jr., Ellis FH, Jr., Tilden RL, Erickson RV. Endoscopic surveillance of Barrett's esophagus: a cost-effectiveness comparison with mammographic surveillance for breast cancer. Am J Gastroenterol 1998;93:911-915. 4 Sampliner RE. Practice guidelines on the diagnosis, surveillance, and therapy of Barrett's esophagus. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1998;93:1028- 1032. 5 Spechler SJ, Goyal RK. The columnar-lined esophagus, intestinal metaplasia, and Norman Barrett. Gastroenterology 1996;110:614-621.
Hung jury on surveillance for Barrett's oesophagus: inadequate data 30 November 2000
Rebecca C Fitzgerald, MRC Clinician Scientist Dept. of Adult & Paediatric Gastroenterology, St. Barts & The Royal London Sch. of Medicine, E1 2AD Send response to journal: Re: Hung jury on surveillance for Barrett's oesophagus: inadequate data	EDITOR-Macdonald et al report their experience of endoscopic surveillance for cancer in a 10 year cohort of patients diagnosed with Barrett’s oesophagus at the Leicester General hospital,(1). This is an update of their previous analysis of these same patients published in 1997. The conclusions from this most recent paper, which includes an analysis of patients diagnosed with Barrett’s oesophagus who did not undergo surveillance, are the same as previously, (2). Specifically, the study found that in this case the current endoscopic surveillance strategy had limited value in diagnosing early cancers occurring in Barrett’s oesophagus patients. This paper, (1) is a useful analysis of the practical difficulties encountered in running a surveillance service for these patients. Surveillance is cumbersome and costly. Furthermore, a significant proportion of these patients may be too unfit to undergo regular endoscopies. However, it is not possible to draw any conclusions from this study as to whether endoscopic surveillance is worthwhile in general as a cancer- screening tool. Firstly, the sample size is too small. A power calculation demonstrates that a sample size of at least 500 patients undergoing surveillance, compared with no surveillance, for at least 5 years is required. Secondly, the ‘no surveillance’ group are inevitably older and female predominant which will affect the likelihood of their developing oesophageal cancer before they die from other conditions. Whilst a randomised control trial is probably unethical, a meta-analysis of the results from those centres performing surveillance compared with those who don’t would indeed be a useful comparison. Thirdly, the definition of Barrett’s oesophagus in this study was not restricted to specialised intestinal metaplasia, which is the group currently recommended to have surveillance by the American Gastroenterology Association. Fourthly, a very limited biopsy protocol was used. Although the authors argue that more extensive biopsies would not have made any difference, this is hard to prove from the data presented, (3). Restricting surveillance to surgically fit patients with specialised intestinal metaplasia, and using a multiple biopsy method with spiked forceps, may significantly improve the yield from such a surveillance programme, (4). It is not that cancers don’t occur in these patients (5/143 or 3.5% in their surveillance cohort developed cancer), it is just that we are not good at detecting them. Better methods are indeed needed to identify patients with Barrett’s at risk of developing cancer, (1,5). Although this paper highlights some of the practical problems with surveillance, it does not further our understanding of how we should move forward. References 1. MacDonald CE, Wicks AC, Playford RJ. Final results from 10 year cohort of patients undergoing surveillance for Barrett’s oesophagus: observational study. BMJ 2000;321:1252-1255. 2. MacDonald CE, Wicks AC, Playford RJ. Ten years’ experience of screening patients with Barrett’s oesophagus in a university teaching hospital. Gut 1997;41:303-307. 3. Fitzgerald RC, WR Burnham. Consideration of histopathological subtypes and biopsy techniques in Barrett’s oesophagus surveillance programmes. Gut 1998; 42 (3):448. 4. Fitzgerald RC, IT Saeed, D Khoo, MJG Farthing. Rigorous surveillance protocol increases the detection of curable cancers associated with Barrett’s oesophagus. Dig Dis Sci in press 5. McGarrity TJ. Barrett’s oesophagus: the continuing conundrum. BMJ 2000;321:1238-1239.
Re: Hung jury on surveillance for Barrett's oesophagus: inadequate data 4 December 2000
R J Playford, Professor of Gastroenterology Imperial College School of Medicine, Hammersmith Hospital Send response to journal: Re: Re: Hung jury on surveillance for Barrett's oesophagus: inadequate data	The title of our article states it is an observational study. The results clearly show the outcome of our patients and the lack of benefit using the protocol outlined in the document. As no statistical comparisons were performed or implied between those participating in the programme and those that did not, the discussion of appropriateness of sample size, power calculation and age difference between the two groups is somewhat irrelevant to our paper. We state that other groups should critically analyse and publish their results so that meta-analyses can be performed. Dr Fitzgerald is therefore repeating what we have already stated as 'the way forward'. Publication bias towards positive results is well recognised and our manuscript reflects the views and practices of many gastroenterologists in the UK. It is difficult to comment on the paper 'in press' by Dr Fitzgerald although we would, of course, be delighted if it fulfils the criteria set by Dr Fitzgerald in providing a trial of 500 patients for 5 years with randomised rigorous versus less rigorous biopsy protocol. If this has occurred, we will be a long way towards showing the benefit (or otherwise) of such an approach. Indeed, we specifically suggest such a comparison in our paper. To provide strong evidence for the benefit of surveillance programmes, it is important that studies use survival as the end point, rather than some surrogate marker such as detection of dysplasia. This is well demonstrated by our paper in which a single patient was identified as having early oesophageal cancer at a surveillance endoscopy, but died postoperatively (and therefore cannot be considered a success). In contrast, one of our patients had a cancer detected at an additional (non-surveillance) endoscopy and appears to have been cured. Enthusiasm to help patients prevent and/or treat cancer is universal. The WHO recommendations mentioned in our paper have been devised as a checklist for appropriateness of such programmes. Behind all the rhetoric from protagonists, the data to change enthusiasm-led protocols to evidence- based medicine is still not available. Since submission of our work, others centres have recently come to a similar, somewhat disappointing, conclusion regarding the value of their programmes. (eg 1). Surely it is not too much to ask that enthusiasts prove their point by showing the results from their own hard labour. Finally, we have fully discussed the rationale for our contention that, in the patients identified in our series, extra biopsies would have been unlikely to help. Full details are provided on the internet for interested readers and we suggest they draw their own conclusions. References 1. Nilsson J, Skobe V, Johansson J, Willen R, Johnsson F. Screening for oesophageal adenocarcinoma: an evaluation of a surveillance programme for columnar metaplasia of the oesophagus. Scand. J. Gastroenterology 2000:35; 10-16
Re: Studies on screening in Barrett's oesophagus must be relevent to modern practice 4 December 2000
R J Playford, Professor of Gastroenterology Imperial College School of Medicine, Hammersmith Hospital Send response to journal: Re: Re: Studies on screening in Barrett's oesophagus must be relevent to modern practice	Dr Beales response provides a useful forum to discuss the current understanding of Barrett's mucosa and areas of confusion. There is a difference between screening and surveillance, they are not interchangeable terms. Our paper examined the benefit of surveillance (i.e. a population who are known to have increased risk) as opposed to screening (i.e. examining a general population to detect an unidentified problem). The original case reports described by Norman Barrett did not mention intestinal metaplasia. However, it is now generally recognised that intestinal metaplasia is an important, and possibly absolute, requirement for the development of adenocarcinoma. It is for this reason that its presence has since been included as part of the criteria for diagnosis. However, it is also now generally accepted that virtually all cases of oesophageal metaplasia containing columnar epithelium will also have areas of intestinal metaplasia if enough samples are taken (N. Shepherd. 'Specialised Intestinal Metaplasia and Dysplasia' 2000 United European Gastroenterology Conference). Dr Beales argument is therefore somewhat circular in nature as, although it was not considered an absolute requirement for entry into the programme, virtually all of our patients will have had intestinal metaplasia present, even if not shown on the biopsies obtained. As discussed in our paper, five oesophageal cancers developed in our surveyed cohort, which is a similar rate to that reported by others. The frequency of cancer development in patients with Barrett's oesophagus is highly debated, the paper stating a higher rate quoted by Dr Beales has no greater status than the one quoted by us. American Gastroenterology Association guidelines have been generated but are not sufficiently evidence-based to prove their value. To blindly follow them without auditing their cost-benefit cannot be considered sensible in the current evidence-based culture. The survey quoted in our paper showed that very few centres in the UK are following the "American" advice; jumbo biopsies, four-quadrant, every 2 cm along the affected area. The histological work load generated by this approach alone being somewhat prohibitive. A recent report from the USA showed that their practice was also far from perfect (as defined as following the USA guidelines) (1). Interestingly, a major factor determining how often these patients were endoscoped and how many biopsies were taken was whether the doctor was being paid as a "fee-for-service" (1). Our article shows that the protocol followed by us (annual surveillance with 4-quadrant biopsies at midpoint plus additional biopsies at strictures or ulcers) did not appear to be beneficial. Many centres in the UK are currently using similar approaches (see response from Dr Ferguson on the BMJ Net as an example). Dr Beales suggestion that our work has only historical interest is therefore erroneous. The British Society of Gastroenterology is currently generating guidelines on Barrett's surveillance. A major problem they are faced with is that they can find very little strong evidence to support recommendations (personal communication). The generation of such guidelines naturally encourages us to follow them as a measure to reduce potential litigation. This is, however, distinct from being sure that were are helping patients. It is important that protagonists of surveillance appreciate the difference and that formal trials are undertaken and reported to allow evidence to be generated. References 1. Gross CP, Canto MI, Hixson J, Powe NR. Management of Barrett's esophagus: a national study of practice patterns and their cost implications. Am J Gastroenterology 1999:94:3440-7.
Biomarkers to refine surveillance of Barrett's oesophagus patients 9 January 2001
Christopher Wild, Professor of Molecular Epidemiology School of Medicine, Univ. of Leeds Send response to journal: Re: Biomarkers to refine surveillance of Barrett's oesophagus patients	Sir, McDonald and colleagues conclude that current surveillance strategies for Barrett's oesophagus patients provide no benefit in terms of reduced risk of mortality from oesophageal adenocarcinoma1. In their annual surveillance programme of 143 patients with an average follow-up period of 4.4 years only one patient was diagnosed with cancer as a result of a biopsy taken within the programme. Thus whilst Barrett's oesophagus confers a 30- to 125-fold increased risk of oesophageal adenocarcinoma compared to unaffected individuals the relatively low absolute incidence of cancer (approx. 1 per 100 patient years)2 results in few cancers being detected by routine surveillance. The authors also suggest that molecular markers may identify patients at greatest risk of developing cancer. This view is supported by our data from a similar surveillance cohort in Leeds, UK using cyclin D1 overexpression as a marker of risk3. In this prospective surveillance cohort, 307 patients with specialised columnar (intestinal) epithelium were included and underwent endocopic examination annually. A total of 12 incident cases of oesophageal adenocarcinoma were detected between 1984 and 1995 with a mean follow-up of 4.3 years. These cancer patients were matched by age, sex, length of columnar epithelium and length of follow-up with up to six patients from the cohort who did not develop adenocarcinoma. The biopsies obtained at recruitment were stained for cyclin D1 overexpression and cases were found to be approximately seven times more likely to be positive for the marker than controls (odds ratio = 6.85; 95% confidence interval = 1.57-29.91; p=0.0106). Whilst these results are promising, there was a significant prevalence of positive cyclin D1 staining in biopsies from Barrett's patients who have not yet developed cancer, 14 of 49 (29%) and, biopsies from 4 of 8 of the Barrett's patients who did develop adenocarcinoma did not stain positive at recruitment. Therefore the sensitivity and specificity of the cyclin D1 marker were 67 and 71% respectively. Nevertheless, if this prevalence of cyclin D1 positive staining applied to the whole cohort and had been used as a criterion for entry into the surveillance programme then approximately 90 subjects would have been subject to follow-up with the detection of eight cancers. Given the fact that multiple genetic alterations are implicated in the natural history of Barrett's oesophagus and adenocarcinoma4 it is possible that a combination of carefully validated biomarkers will improve still further the predictive value of the molecular approach. The rising incidence of the disease and the advances in the understanding of its molecular pathology suggests that it is premature to dismiss refined surveillance programmes for early detection and more effective treatment of this cancer. Professors Christopher Paul Wild and David Forman, Epidemiology and Health Services Research, School of Medicine, University of Leeds, LS2 9JT c.p.wild@leeds.ac.uk 1. Macdonald, C.E., Wicks A.C., and Playford, R.J. Final results from 10 year cohort of patients undergoing surveillance for Barrett's oesophagus: observational study. BMJ, 2000;321:1252-1255. 2. Kim, R., Weissfeld, J.L., Reynolds, J.C., and Kuller, LH. Etiology of Barrett's metaplasia and esophageal adenocarcinoma Cancer Epidemiology, Biomarkers & Prevention 1997;6:369-377. 3. Bani-Hani, K., Martin, I.G., Hardie, L.J., Mapstone, N., Briggs, J.A., Forman, D., and Wild C.P. Prospective study of cyclin D1 overexpression in Barrett's esophagus: association with increased risk of adenocarcinoma. J. Natl. Cancer Inst., 2000;92:1316-1321. 4. Jankowski J.A., Harrison, R.F., Perry I., Balkwill, F., Tselepis, C. Barrett's metaplasia. The Lancet, 2000;356:2079-2085.
surveillance endoscopy should never be discouraged 3 February 2001
Helen Dresner, Reading Coordinator East Meadow School District Send response to journal: Re: surveillance endoscopy should never be discouraged	I would like to differ with the opinion of Drs. MacDonald,Wicks and Playford, with respect to the findings that there is no significant benefit to the frequent surveillance endoscopy which is often suggested with a diagnosis of barretts esophagus. I credit the diligence and patience of my gastroenterologist with his insistence of annual and biannual endoscopy to monitor my esophageal cellular status. I was diagnosed with barretts esophagus in 1993 and was carefully monitored for any changes until 1998. Had it not been for the thorough samplings that my gastroenteroligist suggested, the changes that were found such as questionable dysplasia, low grade dysplasia and eventually a foci of high grade dsyplasia could surely have led to a more serious diagnosis of an invasive adenocarcinoma All my original slides were seen by 4 different pathologists including such well known doctors as, Stanley Hamilton of M.D. Anderson Cancer Reaserch Center, and Noam Harpaz of Mt. Sinai Medical Center. Their consensus indicated that celluar changes were taking place and were noted in their reports. My ultimate need for an esophajectomy and the post colonic interposition pathology report of ONLY high grade dysplasia is a credit to the diligence of the endoscopist who took the time to thoroughly keep on "top" of the changes by mapping the biopsies he completed. I would therefore like to say, that when a person has a diagnosis of barretts esophagus, every effort should be made by the patient's physician to encourage that individual to undergo endoscopy at least annually! This should be done regardless of the length of the barretts measured , as endoscopy can never accurately indicate the exact amount present! Thank you.