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See article on page747
The article by van Laethem et al in this issue (see page 747) describes a well conducted study using the argon plasma coagulator (APC) to treat Barrett’s oesophagus in 31 patients. However, complete eradication of Barrett’s mucosa was only confirmed histologically in 19 (61%), the remainder having a few residual Barrett’s glands under the new squamous epithelium. Seventeen of those with apparent complete endoscopic and histological eradication at early follow up were biopsied again a year later, eight (47%) of whom had relapsing islands of Barrett’s metaplasia despite continuous treatment with omeprazole. These results lead to the same conclusion as that emerging from many recent studies on the endoscopic treatment of Barrett’s oesophagus using a variety of techniques.1-5It is possible to destroy specialised columnar epithelium in the oesophagus with a range of techniques and the treated areas heal with regeneration of squamous epithelium. However, there is a high risk of leaving some Barrett’s glands under the regenerated squamous epithelium. This raises two crucial questions. Firstly, does it matter if a few glands are left behind and, secondly, can any of the treatment options be modified to give reliable destruction of all the Barrett’s glands without any unacceptable complications.
The first question is tackled in the paper, although is very difficult to answer. Statistically, if the number of Barrett’s glands is drastically reduced, one would expect the risk of neoplastic transformation also to be reduced, but this may be an over simplification. Columnar epithelium in the oesophagus could regenerate from the residual glands, and subsequently be vulnerable to neoplastic transformation. Only long term follow up of large numbers of patients such as those treated in this report can answer this question.
In the short term, there is more potential in looking at ways to improve treatment. The key is to find a technique that will destroy the full thickness of mucosa reliably without damaging the underlying muscle. In this paper, it is clear that there is no selectivity of effect between mucosa and muscle. This is not surprising as the biological effect of the APC is just due to local deposition of heat. The same would be expected with any technique that produces its effect by heating the tissue, such as multipolar electrocoagulation or a KTP laser.1 Two patients developed an oesophageal stricture severe enough to require dilatation, presumably because the APC had necrosed some muscle, which healed with scarring. The challenge is thus to deliver enough energy uniformly over the Barrett’s oesophagus to destroy the mucosa but not to damage the muscle. As the narrow beam is moved over the area being treated under direct vision, and the result judged just on the immediate visual effect, I think it unlikely that it will be possible to improve much on the results described in this paper, especially as the thickness of the mucosa may vary with the degree of distension of the oesophagus at the moment each shot is fired.
A technique like photodynamic therapy (PDT) that treats all the mucosa uniformly would be more attractive.2-5 This involves systemic administration of a photosensitising drug and subsequent circumferential illumination of the affected segment of oesophagus with low power red light, usually from a laser. A variety of light delivery devices are being developed for this, including cylindrical transparent plastic devices and balloons with a central diffusing fibre that can be inflated in the oesophagus.2The biological effect is photochemical rather than thermal and relatively sparing of connective tissues like collagen and elastin. However, studies using the photosensitising agent photofrin have shown that, as with the APC, there is no selectivity of necrosis between mucosa and muscle and strictures may occur.2
A more promising photosensitising agent for this application is 5-aminolaevulinic acid (ALA). In vivo, this is converted to the photoactive derivative, protoporphyrin IX (PPIX). In contrast to photofrin, which can be found in all layers of the oesophageal wall, PPIX localises mainly in the mucosa and experimental studies have shown that this can be exploited to give selective necrosis of mucosa without damage to underlying muscle.6 This is exactly what is required to treat circumferential zones of Barrett’s oesophagus. Two important clinical studies have been published using ALA.3 ,4 Neither described any strictures after treatment, which suggests that the muscle layer is not affected, but both reported residual Barrett’s glands under areas of regenerated squamous mucosa, so the problems are not yet all solved. Most clinical studies using ALA in the gastrointestinal tract have reported that the necrosis produced is very superficial using the maximum dose of ALA that can be tolerated by mouth (60 mg/kg, limited by first pass metabolism in the liver).7
Thus the next challenge is to find a way of increasing the depth of mucosal necrosis produced using ALA and seeing if this can be achieved without putting the muscle layer at risk. Options currently being explored are to give ALA intravenously, to increase the tissue concentration of PPIX either by using ALA esters8 or by adding an iron chelating agent (which slows down the final conversion of PPIX to haem),9 and to fractionate the light dose as experimental studies have shown that a single break of 150 seconds part way through illumination can increase the area of necrosis produced by a factor of four.10 However, none of these options has yet got beyond animal studies.
The results reported here by Van Laethem et al are the best that can be expected using the APC. If the few Barrett’s glands remaining after treatment do not matter (and it will be years before we can answer this question), and occasional strictures are acceptable (as they seem to respond well to dilatation), the APC could become the treatment of choice as the procedure is relatively simple, safe and cheap. PDT with photofrin is probably inappropriate for Barrett’s because of the risk of strictures and the long period of skin photosensitivity. It is more appropriate for treating small, locally invasive carcinomas.11 PDT with ALA has the greatest potential for complete destruction of Barrett’s mucosa without causing strictures, but more basic work is required to find out how best to use it.
In the current state of knowledge, it is doubtful whether any form of endoscopic therapy for Barrett’s oesophagus is appropriate other than in the context of clinical trials, unless there is evidence of severe dysplasia and the patient is considered a high risk for surgery. In the latter situation, endoscopic destruction of the mucosa by either thermal or photodynamic therapy can give worthwhile results.