Are there any treatments that prevent progression of BO to cancer?
Are there any treatments that prevent progression of BO to cancer?
Barrett’s Oesophagus arises in individuals with moderate to severe gastro-oesophageal reflux. Treatment of reflux has been recommended to prevent progression to cancer, as have various endoscopic ablation therapies, and the use of COX inhibition. Whilst there is an extensive literature that addresses this issue, only a few randomised trials have evaluated ablation treatments, and no high level evidence is available which addresses the role of anti-reflux treatment or chemoprevention.
Treatment of reflux
Proponents of medical and surgical therapies for the treatment of gastro-oesophageal reflux have at various times recommended the use of proton pump inhibitor medication or antireflux surgery to prevent cancer developing in Barrett’s Oesophagus. Unfortunately there is no high level evidence or randomised trials which support this contention. Whilst clinicians who treat individuals with gastro-oesophageal reflux would like to believe that their treatments make a difference to cancer prevention, evidence supporting this is lacking, and for now decisions to use medication or surgery to treat reflux in individuals with Barrett’s Oesophagus should be based on the need to manage reflux symptoms, rather than cancer risk.
Ablation of Barrett’s Oesophagus
Various endoscopic techniques have been investigated for eradicating Barrett’s Oesophagus epithelium with or without dysplasia (see also What is the appropriate management of low grade dysplasia in patients with BO?, What is the best endoscopic treatment for high grade dysplasia in patients with BO?, What is the best endoscopic management of early oesophageal adenocarcinoma?). Focal ablation techniques (argon plasma coagulation (APC), multipolar electrocoagulation, laser heater probe, and endoscopic mucosal resection (EMR)) and field ablation techniques (photodynamic therapy (PDT) and radiofrequency ablation (RFA)) have been all been described. What is clear from the literature pertinent to this area is that in patients undergoing treatment of gastro-oesophageal reflux by either medical or surgical therapy, the destruction of Barrett’s Oesophagus epithelium, irrespective of the method used, is followed in most individuals by regeneration with a squamous mucosa. However, ablation is often followed by areas of persistent Barrett’s Oesophagus mucosa in the form of Barrett's islands. Further, recurrence of the Barrett’s Oesophagus mucosa occurs in some individuals, and ablation also fails in some individuals. The rationale behind ablation is that it is hoped that the post-ablation squamous mucosa (neosquamous mucosa) has a reduced cancer risk, or even that the risk of cancer is eliminated. The evidence supporting this is limited. The potential for malignancy to arise in islands of retained columnar mucosa or in buried areas of columnar mucosa lying underneath neosquamous mucosa is uncertain, as is the potential for cancer to arise from within the neosquamous mucosa. There has been a case report of cancer arising in neosquamous mucosa, and there have been reports of HGD and oesophageal adenocarcinoma developing following an endoscopically assessed 100% complete eradication response to ablation.
Much of the evidence addressing outcomes following ablation therapy is limited to low quality studies - e.g. uncontrolled case series. However, four randomised controlled trials have compared ablation using PDT, APC or RFA to ongoing endoscopic surveillance.
PDT entails administering a photosensitising drug which sensitises the Barrett’s Oesophagus mucosa to specific wavelengths of light. Light of the appropriate wavelength is then delivered via an endoscope to activate the photosensitiser, and this “burns” the Barrett’s Oesophagus mucosa. Circumferential ablation over a 3-7cm segment length can be achieved. PDT is associated with morbidity including chest pain and odynophagia, photosensitivity, and up to one third of treated patients develop an oesophageal stricture. In countries with strong sunlight such as Australia, this treatment is not practical, and hence it is not available.
In 2005 Overholt et al reported a randomised trial of PDT ablation versus surveillance in patients with Barrett’s Oesophagus and high grade dysplasia (HGD). The trial recruited 208 patients and randomised them 2:1 to PDT versus surveillance. All patients used omeprazole 20mg twice daily for reflux control. The results showed less progression to cancer at five years following PDT (15.2% versus 28.6%), with the risk of cancer halved. Follow-up in the study was incomplete, and one third of the PDT group also developed an oesophageal stricture which required dilatation. However, this trial did show that the risk of malignancy in Barrett’s Oesophagus with HGD can be reduced by endoscopic ablation, although the risk was not eliminated.
Argon Plasma Coagulation (APC)
Argon Plasma Coagulation (APC) ablation is widely available and relatively inexpensive. It uses monopolar electrocautery, via an argon gas stream to carry electrical charge to the closest mucosal surface. This achieves ablation without direct contact. Recently, APC has fallen out of favour as an ablation technique, and it is being replaced by RFA in many parts of the world.
The only randomised trial evaluating APC versus surveillance was conducted in Adelaide. One hundred and twenty six (126) patients with non-dysplastic Barrett’s Oesophagus or low grade dysplasia (LGD) were enrolled into two randomised controlled trials of APC ablation versus endoscopy surveillance. One trial enrolled patients in whom reflux was controlled by proton pump inhibitor therapy, and in the other patients had undergone effective anti-reflux surgery to control reflux. In both studies 95-100% macroscopic (endoscopic) ablation was achieved after two to six treatment sessions. In patients who underwent ablation after fundoplication, a stable neosquamous epithelium was confirmed five or more years after ablation. However, only one patient progressed to high grade dysplasia (HGD) across the follow-up period, and this study failed to demonstrate any role for APC ablation in preventing cancer progression in patients with non-dysplastic Barrett’s Oesophagus.
RFA employs a bipolar array to create an electrical field, which is mounted on either a circumferential balloon-based catheter or an endoscope-mounted device. Ablation is achieved relatively uniformly to a depth of 0.5 to 1 mm. Reported results are generally good, but follow-up in most studies remains short.
Shaheen et al reported a multicentre randomised trial of RFA ablation versus surveillance in 127 patients with dysplastic Barrett’s Oesophagus. Approximately half had HGD, and the remainder has low grade dysplasia (LGD) at enrolment. When assessed 12 months after commencing treatment, complete regression was achieved in 77% following RFA versus 0% in controls, and complete remission of HGD was achieved in 80% of the treated group. RFA ablation was associated with a decreased rate of progression to cancer in the first 12 months, although the number of cancers was small; 1/84 versus 4/43, p=0.04. Three year follow-up was reported two years later. 25% of patients who initially had dysplasia and had complete eradication of intestinal metaplasia developed recurrent Barrett’s Oesophagus. They also reported progression to HGD or Cancer in 4.2% of the ablation group (1.37% per patient per year), and hence concluded that the RFA treated population remains at a significant risk, requiring ongoing endoscopy surveillance.
Phoa et al recently reported a randomised trial of RFA versus endoscopic surveillance in patients with Barrett's Oesophagus and low grade dysplasia. In this study 68 patients underwent RFA ablation versus 68 controls. At 3 years follow-up, progression to high grade dysplasia or cancer was reduced from 18/68 (26.5%) in the control group to 1/68 (1.5%) in the RFA ablation group, offset by a higher complication rate (19.1%) in the RFA group. However, the effect on progression to cancer was less - 6/68 (8.8%) in the control group versus 1/68 (1.5%) following RFA ablation, and cancer progression was not completely prevented following RFA. Of note, the definition of low grade dysplasia in this trial was stringent, and excluded a significant proportion of patients who would currently be diagnosed with low grade dysplasia in Australia. The definition of low grade dysplasia used probably better matches the definition used for high grade dysplasia elsewhere, and for this reason the trial results better reflect RFA treatment for high grade dysplasia in the Shaheen trial, and lend support to ablation for high grade dysplasia, but not low grade dysplasia as currently defined and diagnosed in Australian practice. As with the Shaheen trial, the RFA treated group still remains at risk of cancer progression and require ongoing endoscopy surveillance. Currently Medicare funding for RFA in Australia is only available for patients diagnosed with high grade dysplasia.
Researchers have speculated that COX or COX-2 inhibition might prevent the progression of Barrett’s Oesophagus to cancer, but high quality evidence to support the use of aspirin or COX-2 inhibitors to prevent cancer development remains lacking. Heath et al reported a randomised controlled trial which enrolled 222 patients with Barrett’s Oesophagus to 48 weeks treatment with 200mg per day Celocoxib versus placebo. One hundred patients had dysplastic Barrett’s Oesophagus (either LGD or HGD). No differences were seen for the treated versus control group for the outcomes of dysplasia development, regression of dysplasia, surface area of Barrett’s Oesophagus, or biomarker expression. From these data the authors concluded that the COX-2 inhibitor Celocoxib was ineffective as a preventer of cancer progression in Barrett’s Oesophagus.
In a short term outcome study which included 114 patients, Falk et al evaluated the impact of the proton pump inhibitor esomeprazole with or without aspirin and showed reduced tissue concentrations of prostaglandin E2 in Barrett’s Oesophagus mucosa. From this they concluded that high dose aspirin and esomeprazole as a cancer prevention strategy should be evaluated further. However, whilst showing some interesting laboratory results, the study did not actually address the issue of cancer prevention in a clinically relevant context.
A recent health economic modeling study from Hur et al, claimed that daily aspirin is likely to be cost effective as a chemoprevention agent for preventing cancer progression in Barrett’s Oesophagus. However, the major assumption underlying this study and its conclusions was that aspirin will reduce cancer progression by 50%, but if this cannot be achieved then the model’s outcomes might be very different.
A large randomised controlled trial is being conducted to evaluate the efficacy of aspirin as a cancer preventer in individuals with Barrett’s Oesophagus which has not progressed to HGD, and this study appears powered to give a definitive answer about whether or not aspirin should be recommended for prevention of cancer. This is a four arm trial which is using a 2x2 design, randomising patients to 20mg versus 80 mg per day esomeprazole, and 300mg aspirin versus no aspirin. The study has enrolled 2513 individuals, but follow-up will not complete until 2019. Hence, at present, there remains no high quality evidence to support the use of COX inhibitors as preventers of oesophageal adenocarcinoma in individuals with Barrett’s Oesophagus, and a positive outcome from the large randomised trial is needed before an aspirin based prevention strategy should be recommended to individuals with Barrett’s Oesophagus in the wider community.
There is currently only limited evidence supporting strategies which aim to prevent the development of oesophageal adenocarcinoma in Barrett’s Oesophagus. The choice of antireflux therapy - proton pump inhibitors versus antireflux surgery - has not been shown to influence progression to cancer, although few would argue against aiming for reflux symptom control in individuals with Barrett’s Oesophagus. Interest has been shown in using COX inhibitors, but unless the outcome of the large aspirin chemoprevention trial, when available in 2019, shows benefit, there will be no high level evidence to support the wider use of aspirin in patients with Barrett’s Oesophagus. Ablation therapies have shown benefit in randomised trials, but only in individuals who have already developed dysplasia. In these individuals, the risk of cancer progression appears to be reduced by approximately 50% by both PDT and RFA ablation techniques, but cancer risk is not eliminated. The only randomised trial to evaluate ablation (APC) in non-dysplastic Barrett’s Oesophagus, failed to show benefit for ablation in this group, and for this reason ablation should remain limited to individuals with HGD, who are at imminent and high risk of developing oesophageal adenocarcinoma.
Evidence summary and recommendations
|Ablation of Barrett’s Oesophagus with radiofrequency ablation or photodynamic therapy in individuals who have already developed high grade dysplasia, reduces, the risk of progression to oesophageal cancer by approximately 50%, although cancer progression is not eliminated.||II||, , , , |
|Ablation of Barrett’s Oesophagus should remain limited to individuals with high grade dysplasia in Barrett’s Oesophagus who are at imminent risk of developing oesophageal adenocarcinoma.||B|
The treatment of gastro-oesophageal reflux with either proton pump inhibitors or antireflux surgery has not been shown to influence progression to oesophageal adenocarcinoma.
There is currently no good evidence supporting the use of COX inhibitors for prevention of oesophageal adenocarcinoma.
Issues requiring more clinical research study
- Long term outcome studies for cohorts of patients undergoing endoscopic ablation of Barrett’s Oesophagus are required.
- Long term outcome studies for randomised trials evaluating endoscopic ablation of Barrett’s Oesophagus are required.
- Phillips WA, Lord RV, Nancarrow DJ, Watson DI, Whiteman DC. Barrett's esophagus. J Gastroenterol Hepatol 2011 Apr;26(4):639-48 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21166712.
- Dua KS, Merrill JT, Komorowski R. Neosquamous epithelium after Barrett's ablation: cause for concern? Gastrointest Endosc 2011 Dec;74(6):1424-5 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21429488.
- Prasad GA, Wang KK, Halling KC, Buttar NS, Wongkeesong LM, Zinsmeister AR, et al. Correlation of histology with biomarker status after photodynamic therapy in Barrett esophagus. Cancer 2008 Aug 1;113(3):470-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18553366.
- Shaheen NJ, Overholt BF, Sampliner RE, Wolfsen HC, Wang KK, Fleischer DE, et al. Durability of radiofrequency ablation in Barrett's esophagus with dysplasia. Gastroenterology 2011 Aug;141(2):460-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/21679712.
- Bright T, Watson DI, Tam W, Game PA, Ackroyd R, Devitt PG, et al. Prospective randomized trial of argon plasma coagulation ablation versus endoscopic surveillance of Barrett's esophagus in patients treated with antisecretory medication. Dig Dis Sci 2009 Dec;54(12):2606-11 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19101798.
- Sie C, Bright T, Schoeman M, Game P, Tam W, Devitt P, et al. Argon plasma coagulation ablation versus endoscopic surveillance of Barrett's esophagus: late outcomes from two randomized trials. Endoscopy 2013 Sep 9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24019134.
- Phoa KN, van Vilsteren FG, Weusten BL, Bisschops R, Schoon EJ, Ragunath K, et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. JAMA 2014 Mar 26;311(12):1209-17 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24668102.
- Overholt BF, Wang KK, Burdick JS, Lightdale CJ, Kimmey M, Nava HR, et al. Five-year efficacy and safety of photodynamic therapy with Photofrin in Barrett's high-grade dysplasia. Gastrointest Endosc 2007 Sep;66(3):460-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17643436.
- Overholt BF, Lightdale CJ, Wang KK, Canto MI, Burdick S, Haggitt RC, et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international, partially blinded, randomized phase III trial. Gastrointest Endosc 2005 Oct;62(4):488-98 Available from: http://www.ncbi.nlm.nih.gov/pubmed/16185958.
- Bright T, Watson DI, Tam W, Game PA, Astill D, Ackroyd R, et al. Randomized trial of argon plasma coagulation versus endoscopic surveillance for barrett esophagus after antireflux surgery: late results. Ann Surg 2007 Dec;246(6):1016-20 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18043104.
- Shaheen NJ, Sharma P, Overholt BF, Wolfsen HC, Sampliner RE, Wang KK, et al. Radiofrequency ablation in Barrett's esophagus with dysplasia. N Engl J Med 2009 May 28;360(22):2277-88 Available from: http://www.ncbi.nlm.nih.gov/pubmed/19474425.
- Heath EI, Canto MI, Piantadosi S, Montgomery E, Weinstein WM, Herman JG, et al. Secondary chemoprevention of Barrett's esophagus with celecoxib: results of a randomized trial. J Natl Cancer Inst 2007 Apr 4;99(7):545-57 Available from: http://www.ncbi.nlm.nih.gov/pubmed/17405999.
- Falk GW, Buttar NS, Foster NR, Ziegler KL, Demars CJ, Romero Y, et al. A combination of esomeprazole and aspirin reduces tissue concentrations of prostaglandin E(2) in patients with Barrett's esophagus. Gastroenterology 2012 Oct;143(4):917-26.e1 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22796132.
- Hur C, Nishioka NS, Gazelle GS. Cost-effectiveness of aspirin chemoprevention for Barrett's esophagus. J Natl Cancer Inst 2004 Feb 18;96(4):316-25 Available from: http://www.ncbi.nlm.nih.gov/pubmed/14970280.
- Jankowsk J. A Phase III, Randomized, Study of Aspirin and Esomeprazole Chemoprevention in Barrett's Metaplasia (AspECT). ClinicalTrials.gov 2005 Mar;NCT00357682 Available from: http://clinicaltrials.gov/show/NCT00357682.