Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Mucosa
 The
 Esophagogastric  Junction
 Barrett's
 Esophagus

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OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Dysplasia
 

Should photodynamic therapy be considered as the preferred treatment for high-grade dysplasia?

H. Barr (Gloucester)

Photodynamic therapy (PDT) is an exciting and novel new technique with the potential for selective destruction of dysplastic Barrett's esophagus. It is usually based on the systemic administration of certain photosensitising drugs that are retained with some selectively in rapidly proliferating, dysplastic and frankly malignant tissue. If the sensitised tissue is exposed to the appropriate wavelength of light (often endoscopically applied using a laser fibre) a highly localised cytotoxic reaction occurs. This is mediated by singlet oxygen, and if a threshold photodynamic dose is achieved (related to the light fluence and the tissue photosensitiser concentration), cellular destruction is inevitable. In gastrointestinal tissues the maximum tumor:normal photosensitiser ratio that can be obtained with a variety of photosensitising agents is approximately 2-3:1. Investigation of photodynamic therapy (PDT) in experimental gastrointestinal neoplasms has demonstrated important biological advantages. Full thickness intestinal damage produced by PDT unlike thermal laser damage does not reduce the mechanical strength of the bowel or cause perforation, because the submucosal collagen is preserved [1]. In addition selective necrosis of small areas (less than 2 mm) is possible with preservation of adjacent non-malignant structures [2].

Theoretical and biological considerations

As a technique for the selective mucosal ablation of Barrett's dysplasia or metaplasia there are certain theoretical and biological advantages. Since the photosensitiser may be made to localise in the mucosal layer with relatively little uptake in the underlying muscle. Thus surface eradication is possible and the depth of necrosis may be dependent on the nature of the photosensitiser

The most commonly used method of PDT is to administer a photosensitiser intravenously and allow retention in the tissue for 48 hours prior to irradiation with appropriate wavelength light from the laser. The exogenously administered photosensitisers tend to accumulate in tumor stroma and in the sub-mucosal layer of the gastrointestinal tract. This may be of little relevance if all the mucosa above is destroyed but the depth of damage is of the order of 6mm and stricture formation a distinct hazard

The problem of targeting the photosensitiser to the dysplastic mucosa, and avoiding systemic photosensitisation may be overcome by using endogenous photosensitisation. Following an excess administration of aminolaevulinic acid (ALA), a precursor of haem, an intracellular accumulation of the photosensitiser protoporphyrin IX (PpIX) is induced [3]. The synthesis of ALA from glycine and succinyl-CoA is the first step in porphyrin biosynthesis and ultimately haem. This pathway is tightly regulated by end product inhibition. If excess endogeneous ALA is administered then this regulation is bypassed and an intracellular accumulation of the photosensitiser protoporphyrin IX (PpIX) is induced (Figure 1). The level of photosensitisation is minimised to a few hours and the 5-ALA can be administered orally. The photosensitiser is activated in tissue using 630 nm laser light

Figure 1. The haem synthetic pathway which is exploited to generate the accumulation of the photosensitser Protoporphyrin IX.

from an appropriate light source, such as a KTP pumped dye laser. The choice of photosensitiser is crucial to achieve the depth of necrosis that is required. The use of an exogenous photosensitiser such as PhotofrinŽ or any derivative of di-haematoporphyrin ester/ether will produce damage up to 6 mm. Photodynamic therapy to generate PpIX following oral administration of ALA will only produce necrosis to a depth of 2 mm, ideal for eradication of dysplastic mucosa (Table I).

It is important to examine certain other considerations and examine certain parameters to allow safe destruction and safe healing of dysplastic Barrett's esophagus. First, to what depth should the destruction reach? There is one histopathological report with precise measurements of metaplastic columnar epithelium. These authors report measurement of 100 fixed specimens of Barrett's esophagus and squamous esophageal mucosa [4]. This study is highly informative and demonstrates that columnar-lined epithelium is minimally thicker at 0.5 mm (range 0.39-0.59 mm) than normal squamous mucosa at 0.49 (range 0.42-0.58 mm). It must be remembered that fixing tissue will produce 10% shrinkage and a further 10% reduction occurs during processing. However these data are consistent with our initial measurements of esophageal mucosa using optical coherence tomography [5]. Secondly the healing response of the esophageal tissue is crucial, and healing following PDT and acid reduction is with squamous regeneration.

Table I. Comparison of ALA and Photofrin photodynamic therapy for the eradication of high-grade dysplasia. Data from [6-9].

Results of photodynamic therapy

Two major clinical studies of ALA PDT for the ablation of high-grade dysplasia are reported in full [7, 9]. Both have demonstrated complete eradication of dysplasia. One series also demonstrated the successful eradication of T1 tumors that were less than 2 mm in depth. A prospective randomised trial of the treatment of low-grade dysplasia using ALA and irradiation with green light rather than the usual 630 nm red light has again confirmed how effective this treatment is in reversing dysplasia and metaplasia. Healing proceeded with the regeneration of neosquamous epithelium [10]. A variation of 5-ALA PDT involves the direct endoscopic spraying of the agent combined with sodium bicarbonate as a mucolytic onto dysplastic Barrett's esophagus. A period of time is allowed for local absorption and then the area is irradiated with light. The response following this technique was variable with 2 of 9 patients failing to show any response [11].

There is now consistent data demonstrating the effectiveness of the PhotofrinŽ for the eradication of dysplasia arising in Barrett's esophagus [8]. Treatment schedules involve prior administration of PhotofrinŽ 2 mg/kg forty-eight hours before endoscopic irradiation with light from a laser (630 nm). A windowed centring balloon allows more accurate and even light dosimetry. It is not recommended that more than 7 cms of Barrett's esophagus is treated at one session. Treatment can be performed on an outpatient basis and patients must all received profound acid suppression with proton pump inhibitor therapy. Direct sunlight must be avoided for a period of 4-6 weeks. This is clearly a more aggressive therapy than ALA PDT, and the level of damage is deeper (Table I) and surrounding tissues may be affected. Most patients develop small unilateral or bilateral pleural effusions. Occasionally the patient required a thoracentesis. Cutaneous photosensitivity can be a significant problem up to 2 months after photosensitisation. The major concern has been the incidence of esophageal stricture. Approximately 30% developed significant stenosis that responded to endoscopic esophageal dilatation. The results of PhotofrinŽ-PDT are very encouraging, with 75-80% of the Barrett's mucosa being converted to neosquamous mucosa. Complete eradication of all metaplastic epithelium occurred in 43 of 100 patients. Dysplasia disappeared in 78 of 100 patients, although 11 developed dysplasia during follow-up and required repeat treatment. Thirteen patients were treated for early cancer (T1-12 patients; T2-1 patient), and in ten the tumor was eradicated.

There appear to be three mechanisms for the squamous re-epithelialisation after PDT and other ablation techniques [12]. First encroachment from adjacent squamous epithelium, squamous metaplasia within the Barrett's mucosa itself from pluripotential stem cells, and re-growth from squamous lined ducts of the esophageal mucus gland. It is very important to remember that cancer can occur after neosquamous re-epithelialisation and continued surveillance is essential.

Conclusion

Photodynamic therapy with ALA and PhotofrinŽ is highly effective for the eradication of dysplastic Barrett's esophagus. If cancer is suspected PhotofrinŽ-PDT is more likely to eradicate to a greater depth but with increased morbidity. Thermal ablation techniques appear similar but don't specifically target the mucosa and require prolonged treatment times to treat large areas. It is likely that both PDT and other methods will be used for treatment of dysplastic Barrett's esophagus. There is as yet no definite preferred method of mucosal ablation but PDT remains a leading contender.

References

1. Barr H, Tralau CJ, Boulos PB, MacRobert AJ, Tilly R, Bown SG. The contrasting mechanisms of colonic collagen damage between photodynamic therapy and thermal injury. Photochem. Photobiol 1987;46:795-800.

2. Barr H, Tralau C.J, Boulos PB, Krasner N, Clark CG, Bown SG. Selective destruction of dimethyl-hydrazine rat colon cancer using phthalocyanine photodynamic therapy. Gastroenterology 1990;98:1532-1537.

3. Grant WE, Hopper C, MacRobert AJ, Speight PM, Bown SG Photodynamic therapy of oral cancer:photosensitisation with systemic aminolaevulinic acid. Lancet 1993;342:147-148.

4. Ackroyd R, Brown NJ, Stephenson TJ, Stoddard CJ, Reed MW. Ablation treatment for Barrett oesophagus: what depth of tissue destruction is needed. J Clin Pathol 1999;52:509-512.

5. Bamford K, James J, Barr H, Tatam R. Electromagnetic simulation of laser-induced fluorescence in bronchial tissue and predicted optical scattering behaviour"Optical and Imaging Techniques for Biomonitoring IV(SPIE Proceedings). 1998;3567:18-28.

6. Barr H, Krasner N, Boulos PB, Chatlani PT, Bown SG. Photodynamic therapy for colorectal cancer: a quantitative pilot study. Brit J Surg 1990;77:93-96.

7. Gossner L, Stolte M, Stroke R, et al:Photodynamic therapy of high-grade dysplasia and early stage carcinomas by means of 5-aminolaevulinic acid. Gastroenterology 1998;114:447-455.

8. Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett's esophagus:follow-up in 100 patients. Gastrointest Endosc 1999;49:1-7.

9. Barr H, Shepherd NA, Dix A, Roberts DJH, Tan WC, Krasner N. Eradication of high grade dysplasia in columnar-lined (Barrett's) oesophagus using photodynamic therapy with endogenously generated protoporphyrin IX. Lancet 1996;348:584-585.

10. Ackroyd R, Davis MF, Stephenson TJ, et al. Photodynamic therapy for Barrett's oesophagus: a prospective randomised trial. Endoscopy 1997;29:E17.

11. Ortner M, Zumbusch K, Liebetruth J, et al. Photodynamic therapy in Barrett's esophagus after local administration of 5-aminolaevulinic acid. Gastroenterology 1997;112:A633.

12. Biddlestone LR, Barham CP, Wilkinson SP, Barr H, Shepherd NA. The histopathology of treated Barrett's esophagus. Am J Surg Pathol 1998;22:239-245.


Publication date: August 2003 OESO©2015