What are the compared results of photothermal laser therapy and photodynamic therapy for the eradication of Barrett's esophagus?
H. Barr (Gloucester)
Barrett's (columnar-lined) esophagus is defined as the replacement of the esophageal squamous mucosa by metaplastic specialized columnar glandular epithelium. The condition appears to follow chronic gastroesophageal reflux disease (GERD). Other upper gastrointestinal physiological abnormalities are often present; since not all patients with GERD develop Barrett's esophagus (BE).
Usually the damaged squamous epithelium is repaired by squamous cells. In BE squamous cells are replaced by abnormal columnar epithelium with features of both gastric and intestinal mucosa. The abnormality is clinically important because it predisposes to the development of esophageal adenocarcinoma.
Hypotheses for the photothermal
or photodynamic laser eradication of Barrett's esophagus
I have explored two methods for the eradication of both metaplastic (non-dysplastic) and dysplastic columnar-lined esophagus.
The principles of treatment are:
- destroy all the abnormal epithelium and allow regeneration of the mucosa in an environment where the major precipitating cause (acid reflux) has been controlled;
- control of acid reflux by powerful proton pump inhibitors (omeprazole and lansoprazole).
The constraints of treatment are:
- patients may be completely asymptomatic and healthy. Those with heartburn are often symptomatically controlled by proton pump inhibitors;
- only a proportion of patients with columnar lined esophagus will develop invasive carcinoma;
- "primum non nocere" "first do no harm"; any method that causes perforation, bleeding or serious complications risks the patients life. Less serious complications are also not acceptable to asymptomatic patients.
We present two methods of treatment KTP thermal laser ablation (532 nm) and photodynamic therapy using the KTP pumped dye laser (630 nm).
Background to KTP photothermal laser therapy
The wavelength of the Nd:YAG laser can be reduced to 532 nm by frequency doubling the Nd:YAG laser using a crystal of potassium titanyl phosphate laser (KTP) inserted into the laser. The potassium titanyl phosphate laser (KTP) laser has tissue penetration characteristics that should allow safe thermal treatment of metaplastic and dysplastic columnar lined esophagus. Thermal laser ablation is nonspecific; targeting dysplastic, metaplastic and normal tissue equally. This may be of little consequence providing the depth of damage does not risk perforation and heating occurs without fibrosis and risk of stricture formation. An alternative strategy involves pbotodynamic therapy using the KTP pumped dye laser. The aim would be to directly target the abnormal mucosa, and minimize normal tissue damage. This chapter will examine the use of the KTP laser for the thermal destruction of Barrett's esophagus. In addition the uses photodynamic therapy for the eradication of pre-neoplastic dysplastic columnar lined esophagus is also presented.
Background to photodynamic therapy
Photodynamic therapy (PDT) is an interesting new technique with the potential for selective destruction of cancers. It is based on the systemic administration of certain photosensitising agents, that are retained with some selectivity in malignant tissue. When exposed to appropriate wavelength laser light a cytotoxic reaction occurs causing cellular destruction. In extracranial tissues the maximum tumour:normal ratio that can be obtained with a variety of photosensitising agents is 2-3:1. Investigation of photodynamic therapy in experimental gastrointestinal neoplasms has demonstrated important biological advantages. Full thickness colonic damage produced by photodynamic therapy unlike thermal damage does not reduce the mechanical strength of the bowel or cause perforation, because the submucosal collagen is preserved. In addition selective necrosis of small areas (less than 2 mm) is possible  with preservation of adjacent non-malignant structures. It is clear that this process is limited to small areas of tissue.
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 5-aminolaevulinic acid (5-ALA), a precursor of haem, an intracellular accumulation of the photosensitiser protoporphyrin IX (PpIX) is induced. The synthesis of 5-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 5-ALA is administered then this regulation is bypassed and an intracellular accumulation of the photosensitiser protoporphyrin IX (PpIX) is induced . The level of systemic photosensitisation is minimized to a few hours and the photosensitiser can be administered orally. The photosensitiser is activated in tissue using 630 nm laser light from a KTP pumped dye laser. This study reports the use of this technique to treat patients with high-grade dysplasia in BE.
Methods and patients
KTP laser photodestruction of columnar-lined esophagus
Endoscopic destruction of the superficial mucosa in a non-selective fashion is possible using the laser. It is important to note that the amount of tissue that needs to be ablated is very small and superficial measuring between 1-2 mm. Full thickness or deep damage risks immediate or delayed perforation with the consequences of mediastinitis, peritonitis and death. Damage that does not penetrate to the external surface, yet reaches the muscle causing damage could result in healing by fibrosis and stricture formation. Limitation of the depth of thermal destruction may be important to allow regeneration with squamous rather than columnar cells. The type of epithelium that regrows is in part determined by the depth of injury. For squamous regeneration it is probable that some of the superficial squamous lined ducts must survive. The choice of laser to destroy the tissue is therefore critical.
Three lasers were compared for the thermal destruction of superficial areas of nondysplastic mucosa in the esophagus. A thermal imaging system was used to measure the depth of penetration and the thermal profile in tissue produced using each laser at various powers and energy. The purpose was to find parameters of between than 60-100°C (coagulative necrosis + vaporisation) on the luminal (mucosal) surface with less than 37°C (no risk of full thickness necrosis) on the external surface. The main purpose was to find the laser that would produce damage to the surface mucosa but spare deeper tissue. Patient safety considerations were absolutely paramount, and risk of full thickness damage/perforation avoided at all costs.
The three lasers investigated were the Nd:YAG (1064 nm), KTP (532 nm) and the diode (805 nm). Mounted sections of freshly excised human esophageal tissue were irradiated on a purpose made jig. The imaging system examined the superficial and deep surface, and looked at the thermal profile. The thermal images were stored and thermal plots analyzed at a later date. It is certain that in living tissue the thermal relaxation time of the tissue will be reduced because of blood flow. Thus the temperatures in vivo are unlikely to be rise as much.
Irradiation with the KTP laser, power 15-20W for 1 second produced surface temperatures of greater than 65 °C with external temperature of 21°C. It was extremely difficult to generate high temperatures on the external surface of the esophagus using the KTP laser. The diode laser (25W for 5 seconds) could produce surface temperatures of 90°C but with external temperature of 38°C. The Nd:YAG laser tended to produce worrying temperatures through to the external surface at energy levels that were sufficient to produce thermal destruction on the mucosa.
Patients and methods
For the clinical trial of photodestruction with acid suppression for the eradication of metaplastic (non-dysplastic) BE the KTP laser was chosen as the safest and the one most likely to produce intense superficial destruction only. Eight patients (5 men, 3 women) with a mean age of 58 range 31-74, found at endoscopy for upper gastrointestinal dyspeptic symptoms to have greater than 3 cm of circumferential columnar-lined esophagus have been treated.
All treatments were performed under intravenous sedation with 4-10 mg midazolam, on an outpatient basis. A standard endoscope was used. A 200 micron optical fibre connected to the KTP laser was passed down the instrumentation channel. Safety glass were worn by all personnel and standard laser precautions taken. The operator would thermally destroy all columnar lined esophagus in one segment usually 1/3 to 1/2 of the esophageal circumference. The length of the procedure varied from 10-25 minutes and was dependent on the extent of the BE. The patients received acid suppression with a proton pump inhibitor (omeprazole 20 mg twice a day). Treatment with biopsy was repeated at 6 weekly intervals until all columnar lined esophagus was destroyed. The first two patients were assessed with endoluminal ultrasound prior to and during therapy to see monitor progress. However, it was found not to be able to distinguish treated and untreated areas or normal from columnar-lined esophagus. Its' use was abandoned.
Photodynamic therapy with the KTP pumped dye laser
for the eradication of dysplastic Barrett's esophagus
Seven patients with biopsy proven high-grade dysplasia in BE were given orally,
60 mgkg-1 of 5 amino-laevulinic acid dissolved in fruitjuice or Seven-Up®. After 4 hours, treatment was performed at endoscopy under intravenous sedation with 4-10 mg midazolam. The patients were kept in subdued lighting for 24 hours only. Initial biopsy was taken of the gastric mucosa, dysplastic columnar-lined BE, and normal esophageal wall. The specimens were snap frozen in liquid nitrogen and the uptake of PpIX in these various tissue biopsies studied using quantitative fluorescence microscopy . This demonstrated that PpIX accumulated in dysplastic columnar lined esophagus with little uptake in the adjacent tissue.
All patients were treated using 630 nm light from a dye laser (Laserscope Dye Module 2000, San Jose, California) delivered via a 3 cm cylindrical diffusing fibre, placed in a purpose made 10-14 mm perspex dilator to provide even light distribution. The laser was set to deliver a power of l50mWcm2. An energy fluence of 90-150 Jcm2 was delivered to all areas of BE by repositioning the diffusing fibre. The fields of irradiation will inevitably overlap somewhat as 3 cm segments of esophagus were treated. Acid reflux was suppressed with 40 mg omeprazole daily in divided doses.
Fifty-one laser ablations (mean 4, range 3-8) have been performed in the eight patients
(5 men, mean age 62, range 32-73), who have completed treatment. All treatments have resulted in squamous re-epithelialisation confirmed endoscopically and histologically. In three patients biopsy has demonstrated that squamous epithelium has grown over glandular cells.
Quantitative fluorescence microscopy of the esophageal mucosa demonstrated that dysplastic mucosa accumulated PpIX to a greater degree than the adjacent stroma. It was likely that deep damage to the underlying stromal tissues would be limited. Therefore the risk of stricture formation and perforation would be minimized.
Five patients have completed therapy with photodynamic therapy. Following complete endoscopic treatment follow-up endoscopy and multiple biopsy at 2-month intervals, for 8-30 months, demonstrated squamous regeneration in the dysplastic columnar lined esophagus in four patients with regeneration over metaplastic tissue in two patients. A small area of low-grade dysplasia remained in one patient and was destroyed with KTP thermal laser photoablation.
There were no complications in either groups. Several KTP laser treated patients noticed a transient retrostermal burning pain for 24-48 hours after treatment. There was no evidence of systemic phototoxicity in those treated using photodynamic therapy.
The dramatic rise in the incidence esophageal adenocarcinoma is clearly related to the metaplastic columnar epithelium resulting from chronic reflux damage. Overholt and Panjehpour  have used photodynamic therapy to treated BE containing dysplasia and early carcinoma. They have used intravenous Photofrin as the photosensitiser. This group have done much experimental work and have developed a windowed esophageal balloon in order to improve light dosimetry. Patients with dysplasia and early superficial carcinoma (0-1.5 cms, TIS-1 N-0, M-0) were treated following photosensitisation with porfimer sodium 2 mg/kg. Light (630 nm) was deliver using a windowed centring balloon. Following acid suppression PDT has resulted in squamous regeneration and eradication of dysplasia. However, esophageal stricture easily managed by dilation has occurred in several patients. This indicates that the depth of damage is to the muscular esophageal tube. Laukka and Wang [5, 6] also reported on photodynamic therapy to BE associated with varying degrees of dysplasia. Again squamous regeneration has occurred after acid suppression. In some patients the dysplasia remained unchanged, but 2 and 4 cm displacement of the squamo-columnar junction has been observed. This group again used intravenously administered haematoporphyrin or porfimer sodium.
The attractions of ALA are the oral administration of the photosensitiser, it's rapid excretion and less systemic toxicity. This study demonstrates that endogenous photodynamic therapy with 5-ALA combined with long term omeprazole can eradicate high grade dysplastic columnar lined esophagus and allow regeneration of squamous epithelium. Only long term follow-up of these patients will demonstrate whether the risk of carcinoma is reduced. However, by reversing the dysplastic change it is reasonable to hypothesize that the progressive sequence of worsening dysplasias through to carcinoma has been arrested and at least delayed.
The study of KTP laser eradication of metaplastic columnar lined esophagus confirms an initial clinical study using the argon laser to treat segments of BE . Ten patients had areas metaplastic mucosa destroyed and regeneration was by squamous epithelium after proton pump inhibitor therapy. These results together suggest that multipotential precursor cells in the glandular endothelium can differentiate normally in the correct conditions. The likelihood of achieving complete squamous reepithelialisation was increased by the extent of contiguous squamous borders. Also patches of metaplastic epithelium treated in isolation (not adjacent to squamous mucosa) failed to show squamous re-epithelialisation.
There is experimental evidence that the pattern of regeneration may be mixed. Li et al. suggested that the type of regenerating epithelium is determined by the depth of injury to the mucosa and gland duct . This group after careful examination of histological specimens postulated that stem cells in the esophageal gland possess multipotentiality for cell differentiation. Squamous regeneration may also in part be due to preservation of the squamous lining of upper (superficial 1/3) of the esophageal gland duct. Squamous island regeneration may take its origin from proliferation of this squamous lining. Thus the nature or regeneration may be conditional on the initial depth of injury, and unless some part of the squamous lining in the ducts remains intact squamous regeneration cannot occur. They also point out that the turnover rate of columnar epithelium is approximately five times that of squamous epithelium, thus columnar epithelium may predominate.
It is now clear that BE is a reversible condition. Longer term results are necessary to ensure that the long-term risk of cancer is reduced.
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3. Barr H, Tralau CJ, MacRobert AJ, Morrison I, Phillips D, Bown SG. Fluorescence photometric techniques for determination of microscopic tissue distribution of phthalocyanine photosensitisers for photodynamic therapy. Lasers Med Sci l988;3:81-86.
4. Overholt BF, Panjehpour M. Barrett's esophagus: photodynamic therapy for the ablation of dysplasia, reduction of specialized mucosa and treatment of superficial esophageal cancer. Gastrointest Endosc 1995;42:64-70.