ABSTRACT

The incidence of oesophageal carcinoma is steadily increasing in many western countries in the last 30 years. A current hypothesis is that the majority of these adenocarcinomas arise in a Barrett`s oesophagus, following a sequence from metaplasia through dysplasia to carcinoma. A Barrett`s oesophagus is characterised by the presence of columnar epithelium with intestinal metaplasia in the distal oesophagus. At present, both endoscopic surveillance and oesophageal resection are recommended for patients with Barrett`s oesophagus and high-grade dysplasia. Photodynamic therapy (PDT) with use of 5-aminolevulinic acid (ALA) is a new treatment option ideally leading to endoscopic ablation of the Barrett`s mucosa. PDT involves systemic administration of a photosensitiser to accumulate in the target tissue. Subsequent illumination with light of a specific wavelength, absorbed by the photosensitiser, results in a photochemical reaction that destroys the sensitised tissue. ALA is not a photosensitiser by itself, but a naturally occurring intermediary in the haem biosynthetic pathway. It is metabolised at tissue level to the endogenously photoactive agent protoporphyrin IX (PpIX). ALA induced PpIX seems to accumulate in tumour tissue, glands and cells that line surfaces, such as gastrointestinal mucosa. Therefore, ALA-PDT is worth investigating in the Barrett`s oesophagus. We extensively studied the pharmacokinetics of ALA administered per os and intravenously in rats, by protein and porphyrin measurements and fluorescence microscopy. ALA concentration was highest in the kidney, bladder and urine and, after per os administration also in the jejunum. Porphyrins accumulated mainly in duodenal aspirate, jejunum, liver and kidney. ALA pharmacokinetics was also studied in rats with a Barrett`s oesophagus. It appeared that the selectivity of ALA-induced PpIX accumulation lies in the difference between epithelium and the muscle layers, rather than between squamous and Barrett`s epithelium. Thus, ALA induced endogenous photosensibilisation seems highly suitable for Barrett`s oesophagus, since for the treatment of oesophageal lesions it is more important to preserve the muscle layer than the fast regenerating adjacent normal squamous epithelium. The illumination and the position of the laser fibre finally determine the selectivity of the treatment. It was shown that the illumination parameters determine to a great extent the results of ALA-PDT. The first important factor is the time interval between ALA administration and subsequent illumination. For the oesophagus there is a narrow time interval in which illumination should be performed, which determines the extent of epithelial destruction and the occurrence of side effects. Illumination at 2 h after oral administration of ALA resulted in maximal epithelial damage, whereas illumination at 4, 6 or 12 h resulted in oesophageal dilatation, functional impairment and less epithelial damage. Second, the laser parameters are important for the outcome of the treatment. Wavelength, total light dose and power output need to be chosen accurately; a wavelength of 633 nm combined with a relatively low power output dramatically increased the induced epithelial damage in the oesophagus, compared to a high power output or 532 nm light. Additionally, fractionated light delivery is thought to increase the effect of PDT. Other studies found increased damage using fractionated illumination. However, we found no difference in damage after PDT between fractionated and continuous illumination. The results from the presented studies cannot directly be translated to the human situation, since the optimal parameters are different in man and rat. But important information regarding pharmacokinetics, mechanism, optimisation and caveats of ALA-PDT is obtained.