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The effect of photodynamic therapy (PDT) on oesophageal motility and acid clearance in patients with Barrett’s oesophagus
Journal of Photochemistry and Photobiology B: Biology 85 (2006) 17–22 www.elsevier.com/locate/jphotobiol
The effect of photodynamic therapy (PDT) on oesophageal motility and acid clearance in patients with Barrett’s oesophagus J. Globe b
a,*
, A. Smythe b, C.J. Kelty a, M.W.R. Reed a, N.J. Brown a, R. Ackroyd
b
a Academic Unit of Surgical Oncology, University of Sheffield, UK Department of Surgery, Academic Unit of Surgical Oncology, Floor K, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK
Received 27 February 2006; received in revised form 7 April 2006; accepted 7 April 2006 Available online 24 May 2006
Abstract Background: Barrett’s oesophagus is the major risk factor for oesophageal adenocarcinoma. It is proposed that long-term re-epithelialisation, which has been achieved following ablation using 5-aminolaevulinic acid (5-ALA) photodynamic therapy (PDT) may reduce the risk of malignant change. However, it is not known whether PDT modifies oesophageal motility. Aim: To assess oesophageal pH and motility before and after PDT ablation in treated and untreated areas of the oesophagus. Methods: Twelve patients (10 male) with Barrett’s oesophagus, median segment length 4 cm, were treated with PDT ablation. Twentyfour hours pH assessment and oesophageal manometry were performed before and 4–6 weeks after ablation. PDT was carried out using 635 nm red light, 4–6 h after administration of 30 mg/kg 5-ALA. Proximal (untreated) and distal (treated) oesophageal resting pressure, wave amplitude, percentage peristalsis and percentage study time oesophageal pH < 4, were assessed. Proton pump inhibitors (PPI) were administered throughout the study. Results: There were no significant differences in oesophageal motility in treated or untreated areas of the oesophagus after PDT compared to pre-treatment values. Patients who continued to experience oesophageal acid exposure required more treatments to achieve complete Barrett’s ablation. Conclusions: Oesophageal motility following ALA-PDT suggests a trend toward enhanced wave propagation however continued oesophageal acid exposure may affect PDT efficacy. 2006 Elsevier B.V. All rights reserved. Keywords: Barrett’s oesophagus; Oesophageal motility; Photodynamic therapy; ALA; Argon beam plasma coagulation
1. Introduction Oesophageal motility is often impaired in Barrett’s oesophagus, the level of impairment increasing with the Barrett’s segment length [1,2]. Controversy exists as to whether pre-existing disturbed motility leads to metaplasia, or if it occurs in response to prolonged mucosal injury. Poor oesophageal clearance increases oesophageal exposure to the presence of any noxious refluxate, therefore any treatment that reduces oesophageal motility and the
*
Corresponding author. Tel.: +44 114 2713223; fax: +44 114 2713314. E-mail address: J.Globe@sheffield.ac.uk (J. Globe).
1011-1344/$ - see front matter 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jphotobiol.2006.04.001
efficacy of clearance mechanisms may have the potential to increase the risk of adenocarcinoma. Several different modalities are currently employed to treat Barrett’s oesophagus including proton pump inhibitor (PPI) therapy, anti-reflux surgery and mucosal ablation. Gastric acid suppression using a variety of PPI’s has been the predominant means of reducing both the volume and the acid content of reflux [3]. However, this fails to address the problem of duodeno-gastro-oesophageal reflux (DGOR), and the greatest complications have been seen to occur with concomitant acid and alkaline reflux [4]. Gastric acid suppression may reduce oesophageal clearance mechanisms resulting in prolonged oesophageal exposure to alkaline reflux [5], since the presence of acid within the
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oesophagus stimulates a number of receptors (mechanoreceptors, baroreceptors and chemoreceptors) to initiate both primary and secondary peristalsis to clear any refluxate [6– 8]. Neither gastric acid suppression nor anti-reflux surgery has been shown to achieve regression of the Barrett’s epithelium, or a reduction in the incidence of malignancy [9–11]. In contrast, mucosal ablation aims to reduce the risk of oesophageal adenocarcinoma by inducing squamous reepithelialisation. Several ablation therapies have been employed, including photodynamic therapy (PDT) and argon plasma coagulation (APC). Following randomised placebo controlled clinical trials using ALA-PDT [12] we have demonstrated long- term (5 years) mucosal re-epithelialisation in Barrett’s Oesophagus [13]. However, evidence of the effect of ablation therapy on oesophageal motility appears to be contradictory. The only PDT study published to date suggested that this therapy may be detrimental to oesophageal motility in some patients, possibly due to mucosal inflammation, scarring and fibrosis, or to systemic effects such as cytokine activation [14]. However, this study selected a mixed group of patients, including those with Barrett’s oesophagus and oesophageal carcinoma, and employed photofrin, a photosensitiser which accumulates both within the submucosa and muscularis mucosa, causing deeper tissue injury [15,16] when compared to ALA-PDT where the accumulation of the photosensitiser is restricted to the oesophageal mucosa [17,18]. A small study investigating the effects of APC on motility demonstrated that peristaltic amplitude may increase [19]. The choice of photosensitiser and the application of light during PDT can affect the depth of tissue injury due to photosensitiser accumulation and localisation, the wavelength required for activation (and therefore depth of treatment achieved) [20,21] and the degree of fibrosis that ensues; consequently, oesophageal contractility may also be affected by the same mechanism. It has been shown that mucosal injury resulting in oesophageal stenosis with the possible formation of stricture, may raise the oesophageal resting pressure [22]. Any reduction in the efficacy of oesophageal clearance mechanisms may prevent re-epithelialisation and promote further mucosal change. The primary aim of this study was to investigate the effects of ALA-PDT (30 mg/kg) on oesophageal motility and acid clearance in Barrett’s oesophagus, as there are no previously published studies. Motility was compared in treated (distal) and untreated (proximal) areas of the oesophagus, in addition to an assessment of 24 h pH, made prior to PDT treatment and after complete ablation was achieved, as identified by histological evaluation. 2. Materials and methods Research ethics committee approval was gained (South Sheffield Research Ethics Committee; Reference number 00/031) for this study. Informed written consent was obtained from 12 patients (10 males and 2 females, median
age 56 (range 51–81), all with biopsy proven metaplastic Barrett’s oesophagus recruited from a cohort undergoing endoscopic ablation in a clinical trial comparing PDT with APC [23]. The median Barrett’s segment length was 4 cm (range of 2–6 cm). All patients were administrated esomeprazole (Nexium, Astra Zeneca, UK) 40 mg daily throughout the trial. Prior to the study PPI therapy had been administered for at least 12 months and continued after the trial. Oesophageal manometry and 24-h pH studies were performed before the initial PDT treatment. PDT was repeated at 4–6 week intervals using 5-ALA 30 mg/kg and 635 nm red light until both macroscopic appearance and biopsies taken for histological assessment confirmed complete ablation. Assessment was carried out by a single experienced pathologist using modified Seattle criteria. Previous studies have shown that repeated treatments [23] with these parameters enhance Barrett’s regression when compared to a single PDT treatment [12]. The oesophageal manometry and 24-h pH study were repeated 4–6 weeks after complete ablation was achieved and an assessment was made of any differences in motility. 2.1. Oesophageal manometry A 9-lumen oesophageal catheter (Oakfield Instruments Ltd, Oxon, UK) was connected via transducers to water perfused manometry equipment (Albyn Medical, Dingwall, Ross-shire, Scotland – Phoenix system). Four radially spaced ports (90 apart) were positioned 5 cm from the catheter tip. Further ports were positioned longitudinally at 5 cm intervals along the catheter, which were also circumferentially orientated at 90 to adjacent ports. The catheter was introduced via the nares with the patient seated. Initially all of the ports were placed into the stomach. The manometry continued with the patient recumbent and the mid-axillary line level with the pressure transducers. The catheter was pulled back at 1 cm intervals until the four level ports nearest to the tip were placed within the lower oesophageal sphincter (LOS). The catheter was held in this position with micropore tape while 10 · 10 ml boluses of water were given orally at approximately 30 s intervals. Oesophageal function in both the untreated proximal oesophagus and the treated distal oesophagus was assessed by oesophageal manometry both before the start of treatment and after PDT ablation was achieved. Measurements were taken from the proximal untreated area, approximately 15 cm above the area of the LOS showing the highest pressure, and from the distal, treated area of the oesophagus, approximately 5 cm above the highest pressure point of the LOS. Following complete ablation, 4–6 weeks later, a second manometry evaluation was carried out. A standard oesophageal manometry protocol was used [24]. Mean mid-respiratory cycle pressure measurements were obtained (in cm H2O) and the following parameters measured: (1) Baseline lower oesophageal sphincter (LOS) pressure, (absolute pressure minus the gastric pressure); (2)
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length and location of the LOS; (3) diaphragm location seen on rapid deep inspiration; (4) mean peak contraction amplitude; (5) percentage peristalsis (percentage of wet swallows that generated peristaltic contractions; (6) resting (basal) oesophageal pressure, (a mid-respiratory measurement excluding any contractions). Waves were identified as peristaltic or non-peristaltic (simultaneous or absent). Peristaltic contractions with amplitudes <14 cm H2O were disregarded. After administration of a water bolus, a wet swallow was regarded as successful if it propagated an un-interrupted, peristaltic wave of contractions with amplitudes >30 cm H2O. 2.2. 24-h pH measurement The trans-nasally introduced pH electrode was secured with the tip positioned in the untreated area of the oesophagus, approximately 5 cm above the proximal border of the lower oesophageal sphincter. The location and length of the lower oesophageal sphincter had been established during the preceding manometry. Flexisoft 2 pH analysis software (Oakfield Instruments Ltd, Oxon, UK) was used to analyse the pH data. Meal times were excluded from the analysis. The number of acid reflux episodes were calculated and acid exposure (pH < 4) was determined as a percentage of the supine and upright periods. Patients continued PPI therapy (40 mg esomeprazole daily) during the 24 h oesophageal pH assessment. 2.3. PDT protocol The chosen photosensitiser was 5-aminolaevulinic acid (5-ALA), which preferentially accumulates in the mucosa [17,18]. ALA, a pro-drug, has no intrinsic photosensitising properties but is a metabolic precursor that is converted to protoporphyrin IX (PPIX), an endogenous photosensitiser in the haem biosynthetic pathway, [25]. An oral dose of 5ALA (DUSA Pharmaceuticals, Valhalla, NY, USA) was administered at 30 mg kg 1 4–6 h prior to laser endoscopy. We have previously determined that 30 mg kg 1 is as effective as 50 mg kg 1, produces similar amounts of PpIX and has less systemic toxicity [26]. Each patient underwent an endoscopy using an Olympus XQ240 Video endoscope (Olympus, Tokyo, Japan) with intravenous sedation, analgesia and anti-emetic (midazolam, fentanyl and ondansetron). To facilitate circumferential treatment of the affected area, a windowed balloon applicator (Wizard X-cell PDT balloon, Wilson Cook Medical, Winston-Salem, NC, USA) was used. A non-thermal monochromatic laser light was emitted from a cylindrical diffuser fibre (Pioneer Optics Company, Windsor Locks, CT, USA). The treatments employed 635 nm red laser light (Ceralas 635 nm 3 W diode laser, Biolitec AG, Germany) which was delivered at a fluence rate of 68 mW/cm2 and a total light dose of 85 J cm 2. The fluence rate delivered was calculated from the output power of the light source and the surface area
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of the balloon. The parameters were also informed by previous studies [26,27]. Biopsies were taken at endoscopy 4 weeks after treatment. If residual Barrett’s mucosa was identified, further treatments were repeated at 4–6 weekly intervals until complete ablation was achieved, confirmed by histology. 2.4. Power calculation and statistics A sample size calculation was performed for paired data, using Sampsize Version 2.0 software. Long term clinical experience and unpublished data from our laboratory suggests that patients with Barrett’s oesophagus have P25% reduction in their mean contraction amplitude in the distal oesophagus compared to normal controls. Calculations were made based on a clinical significant difference of a 25% change in oesophageal pressure after treatment, with a power of 80% and a significance of 5%, which indicated that 11 patients were required. Statistical analysis was performed using the Wilcoxon signed rank test for paired, non-parametric data (Table 1). 3. Results 3.1. Manometry Oesophageal manometry was performed prior to the PDT treatment and compared to manometry after successful ablation was achieved (Table 1). Both proximal and distal areas of the oesophagus were included in the manometry. Patients in this study, pre- treatment, had essentially normal manometric values, except for reduced amplitude distal contractions, which is not unusual for patients with Barrett’s oesophagus [1]. The ALA-PDT did not induce any strictures and oesophageal resting presTable 1 Oesophageal motility in 12 Barrett’s patients, before and after 5-ALA PDT ablation Before PDT Untreated proximal area Oesophageal mean resting pressure (cm H2O) Contraction mean peak amplitude Peristalsis% Treated distal area Oesophageal mean resting pressure (cm H2O) Contraction mean peak amplitude Peristalsis% Lower oesophageal sphincter pressure (above gastric) Swallows Percentage successful swallows
After ablation
2 (4)a
1 (4)
NSb
50 (15) 73 (35)
54 (26) 78 (27)
NS
1 (5)
1 (4)
NS
71 (22) 76 (27) 19 (10)
60 (27) 81 (18) 19 (6)
NS NS NS
70% (30)
80% (20)
NS
NS = Not significant. a Results expressed as mean (standard deviation). b Statistical analysis performed using the Wilcoxon signed rank test for paired, non-parametric data. Statistical significance was assigned at the 5% level (p < 0.05).
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Table 2 Twenty-four hours pH in 12 Barrett’s patients before and after 5-ALA PDT ablation Untreated area
Acid exposure (% Study time pH < 4) Upright Acid exposure (% Study time pH < 4) Supine Reflux episodes Symptom index a
Before PDT
After ablation
2.2 (5)a 6.1 (12) 11 (18) 0
1.2 (2) 1.1 (2) 5 (6) 0
Results expressed as mean (standard deviation).
sures were not raised in either the treated or the untreated areas after PDT ablation. After PDT treatment there was a slight, although not statistically significant improvement in peristaltic wave propagation and in the number of successful swallows. The LOS pressures were within the normal range before and after PDT – see Table 1. 3.2. pH measurements There were no differences in total oesophageal acid exposure (expressed as a percentage of the total study time), or in the mean number of reflux events, after ALA PDT ablation compared to pre-treatment values, in either the upright or supine position (Table 2). Meal times were excluded from the pH analysis. Despite treatment with proton pump inhibitors, three of the twelve patients had breakthrough acid reflux resulting in an oesophageal pH below 4. The number of reflux episodes seen in these three patients were 62, 10, and 18, however, following successful ALA-PDT ablation. this was reduced to 6, 7 and 0, respectively. The total percentage oesophageal acid exposure time in these three individuals before PDT was 7.4%, 12.4%, and 12.9%. After ablation, the percentage acid exposure times were reduced to 0.9%, 4.4% and 0%, respectively. This study showed that for the entire group (n = 12) the median number of PDT treatments needed to achieve ablation was two. However the three individuals with persistent oesophageal acid exposure required a median number of four PDT treatments to achieve complete ablation – see Table 2. 4. Discussion This is the first study to show that ALA-PDT does not impair oesophageal motility indeed there may be a trend toward an increase in fully propagated waves and percentage of successful swallows following treatment, although not significant in this small study. The metaplastic response of the oesophageal mucosa to noxious stimuli is replacement of the stratified squamous epithelium with an intestinalised columnar epithelium, (Barrett’s oesophagus). Factors important to establishing a noxious free oesophageal environment are an effective gastro-oesophageal barrier and good oesophageal clear-
ance. Gastro-oesophageal reflux occurs physiologically; however, normally this is cleared rapidly from the oesophagus, due to stimulation of receptors within the oesophageal mucosa, which invoke peristalsis. In patients with reflux disease and/or Barrett’s oesophagus, this mechanism is impaired resulting in failure of acid clearance [6,28]. Successful squamous re-epithelialisation requires an acid free environment and so PPI’s are usually taken throughout ablation therapy [29]. The long-term (>5 years) mucosal re-epithelialisation of Barrett’s patients treated with ALA-PDT [13] observed in our previous studies could be due to maintenance of normal physiological motility [30]. To determine the effect of ALA-PDT ablation therapy on oesophageal function, oesophageal resting pressure, percentage peristalsis, contraction amplitude, lower oesophageal sphincter pressure and total oesophageal acid exposure expressed as a percentage of time (over 24 h) were quantified. Previous studies utilising oesophageal video fluoroscopy and manometry have demonstrated that contraction amplitudes <20 mm Hg may fail to propel a bolus adequately [31,32]. Any impairment in peristalsis or significant reduction in contraction amplitude may result in reduced oesophageal clearance, particularly whilst supine [33]. Patients in this study had essentially normal manometric measurements prior to PDT [30], however fully propagated waves and successful swallows were reduced. It is generally accepted that in the normal population during a standard pull through manometry P80% of wet swallows should generate peristaltic waves that are fully propagated (transmitted to the distal oesophagus). Results from this study showed that before ablation, only 70% contractions were transmitted to the distal oesophagus but after complete ablation this increased to lie within the normal range of 80%. This suggests that motility was not detrimentally affected by the PDT ablation. Infact there was a slight, but not statistically significant improvement in the percentage of propagated peristaltic contractions and number of successful swallows. Lower oesophageal sphincter pressures were unaltered by PDT ablation. Normal physiological manometric values were maintained following ALA PDT mucosal ablation. Any significant rise in either oesophageal resting pressures or lower oesophageal sphincter pressure could indicate the development of a stricture, which can be a complication of Barrett’s oesophagus or as a result of the ablation therapy [34]. In the current study, none of the patients developed a stricture and their oesophageal resting pressures and lower oesophageal sphincter pressures remained unchanged after treatment. Oesophageal acid exposure over a 24-h period was assessed as a percentage of study time. The patients all received PPI therapy throughout the entire study period, thus only patients who were either resistant to PPI’s, non-concordant with treatment, or receiving inadequate gastric acid suppression should exhibit any oesophageal acid exposure. This was the case for nine patients in the
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group, but in three patients, considerable oesophageal acid exposure was monitored despite PPI therapy prior to PDT treatment. An increase in acid exposure following treatment may indicate deterioration in acid clearance mechanisms or in the effectiveness of the gastro-oesophageal barrier. In the nine patients exhibiting normal oesophageal pH, this was maintained following treatment. However, in the three patients with continued oesophageal acid exposure, a marked reduction in acid was observed following successful ablation. These three patients required twice the median number of PDT sessions to achieve complete ablation, than the remainder that did not demonstrate any PPI breakthrough oesophageal acid exposure. This may suggest that oesophageal clearance mechanisms had improved slightly despite no statistically significant difference in oesophageal contraction amplitudes or percentage peristalsis. However due to the small patient numbers, firm conclusions cannot be made. The PDT treatment involved administration of 30 mg/ kg oral ALA 4 hours prior to light treatment, using, parameters determined from previous studies [26,27] demonstrating therapeutic efficacy. The issue of fluence rate and total fluence for optimal PDT response remains controversial and is influenced by a number of factors including the photosensitiser used and the geometry of the treatment area. One study using Photofrin-PDT demonstrated an increased incidence of stricture following treatment with a high light dose (115 J/cm [35]). A further study demonstrated that due to the light scattering in hollow organs there is an increase in the actual fluence rate at the oesophageal wall in vivo, suggesting that the delivery of high light fluence rates is not required [36]. This observation is supported by in vitro light dosimetry studies using an optical phantom, which demonstrated increased light fluences measured by an isotropic detector, when compared to the delivered fluence from the laser fibre [37]. In the current study, the number of PDT treatments required to achieve complete ablation, was not dependent on the total light dose received. Several studies have suggested that many GORD patients are resistant to PPI’s for a variety of reasons including failure of the proton pump, patient non-concordance and drug/drug interactions [38–41]. Currently, there is a lack of data regarding the prevalence of PPI resistance generally, as studies have tended to be carried out on select groups. Frequently patients with Barrett’s oesophagus are no longer symptomatic and are consequently reluctant to continue acid suppressive medication. In this study, all patients were asymptomatic, even during episodes of acid reflux. It is important that patients with Barrett’s oesophagus understand that oesophageal insensitivity often accompanies progression of their condition and that PPI therapy compliance is essential. Our study reinforces the importance of 24-h pH evaluation to establish adequate gastric acid suppression is occurring [42]. A suitable PPI, administered at an adequate dose to accomplish gastric acid suppression prior to ablation
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may be required to reduce the number of PDT sessions to achieve mucosal ablation. This has risk and financial implications. In conclusion, 5-ALA-PDT does not impair oesophageal motility and fewer ablative treatment sessions may be required to achieve complete ablation if adequate gastric acid suppression is achieved with PPI therapy. Acknowledgements The BUPA Foundation, Yorkshire Cancer Research and the Royal College of Surgeons of Edinburgh funded Mr Clive J. Kelty. CSUH Research Department also provided financial assistance. Authors would like to acknowledge Dr. T.J. Stephenson, Dept. of Histopathology, Royal Hallamshire Hospital, Sheffield, UK, for performing the histology assessments. References [1] P. Singh, R.H. Taylor, D.G. Colin-Jones, Esophageal motor dysfunction and acid exposure in reflux esophagitis are more severe if Barrett’s metaplasia is present, Am. J. Gastroenterol. 89 (3) (1994) 349–356. [2] H.J. Stein, S. Hoeft, T.R. DeMeester, Functional foregut abnormalities in Barrett’s esophagus, J. Thorac. Cardiovasc. Surg. 105 (1) (1993) 107–111. [3] J.E. Richter, Duodenogastric reflux-induced (alkaline) esophagitis, Curr. Treat. Options Gastroenterol. 7 (1) (2004) 53–58. [4] R.M. Bremner, P.F. Crookes, T.R. DeMeester, J.H. Peters, H.J. Stein, Concentration of refluxed acid and esophageal mucosal injury, Am. J. Surg. 164 (5) (1992) 522–526, discussion 526-7. [5] W. Meyer, F. Vollmar, W. Bar, Barrett-esophagus following total gastrectomy. A contribution to it’s pathogenesis, Endoscopy 11 (2) (1979) 121–126. [6] M.N. Schoeman, R.H. Holloway, Integrity and characteristics of secondary oesophageal peristalsis in patients with gastro-oesophageal reflux disease, Gut 36 (4) (1995) 499–504. [7] E. Corazziari, E. Materia, C. Pozzessere, F. Anzini, A. Torsoli, Intraluminal pH and oesophageal motility in patients with gastrooesophageal reflux, Digestion 35 (3) (1986) 151–157. [8] I. Bontempo, L. Piretta, E. Corazziari, F. Michetti, F. Anzini, A. Torsoli, Effects of intraluminal acidification on oesophageal motor activity, Gut 35 (7) (1994) 884–890. [9] J.A. Jankowski, M. Anderson, Review article: management of oesophageal adenocarcinoma – control of acid, bile and inflammation in intervention strategies for Barrett’s oesophagus, Aliment Pharmacol. Ther. 20 (Suppl. 5) (2004) 71–80, discussion 95-6. [10] S. Haag, S. Nandurkar, N.J. Talley, Regression of Barrett’s esophagus: the role of acid suppression, surgery, and ablative methods, Gastrointest. Endosc. 50 (2) (1999) 229–240. [11] N.A. Shepherd, Barrett’s oesophagus and proton pump inhibitors: a pathological perspective, Gut 46 (2) (2000) 147–149. [12] R. Ackroyd, N.J. Brown, M.F. Davis, T.J. Stephenson, S.L. Marcus, C.J. Stoddard, A.G. Johnson, M.W. Reed, Photodynamic therapy for dysplastic Barrett’s oesophagus: a prospective, double blind, randomised, placebo controlled trial, Gut 47 (5) (2000) 612–617. [13] R. Ackroyd, C.J. Kelty, N.J. Brown, T.J. Stephenson, C.J. Stoddard, M.W. Reed, Eradication of dysplastic Barrett’s oesophagus using photodynamic therapy: long-term follow-up, Endoscopy 35 (6) (2003) 496–501. [14] N. Malhi-Chowla, H.C. Wolfsen, K.R. DeVault, Esophageal dysmotility in patients undergoing photodynamic therapy, Mayo Clin. Proc. 76 (10) (2001) 987–989.
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[29] R.E. Sampliner, B. Fennerty, H.S. Garewal, Reversal of Barrett’s esophagus with acid suppression and multipolar electrocoagulation: preliminary results, Gastrointest. Endosc. 44 (5) (1996) 532–535. [30] J.E. Richter, W.C. Wu, D.N. Johns, J.N. Blackwell, J.L. Nelson 3rd, J.A. Castell, et al., Esophageal manometry in 95 healthy adult volunteers. Variability of pressures with age and frequency of abnormal contractions, Dig. Dis. Sci. 32 (6) (1987) 583–592. [31] J. Ren, B.T. Massey, W.J. Dodds, M.K. Kern, J.G. Brasseur, R. Shaker, et al., Determinants of intrabolus pressure during esophageal peristaltic bolus transport, Am. J. Physiol. 264 (3 Pt 1) (1993) G407– G413. [32] P.J. Kahrilas, W.J. Dodds, W.J. Hogan, Effect of peristaltic dysfunction on esophageal volume clearance, Gastroenterology 94 (1) (1988) 73–80. [33] M. Simren, J. Silny, R. Holloway, J. Tack, J. Janssens, D. Sifrim, Relevance of ineffective oesophageal motility during oesophageal acid clearance, Gut 52 (6) (2003) 784–790. [34] B.F. Overholt, M. Panjehpour, D.L. Halberg, Photodynamic therapy for Barrett’s esophagus with dysplasia and/or early stage carcinoma: long-term results, Gastrointest. Endosc. 58 (2) (2003) 183–188. [35] M. Panjehpur, B.F. Overholt, M.N. Phan, J.M. Haydeck, Optimization of light dosimetry for photodynamic therapy of Barrett’s esophagus: efficacy vs. incidence of stricture after treatment, Gastrointest. Endosc. 61 (1) (2005) 13–18. [36] R.L. van Veen, M.C. Aalders, K.L. Pasma, P.D. Siersema, J. Haringsma, W. van de Vrie, E.E. Gabeler, D.J. Robinson, H.J. Sterenborg, In situ light dosimetry during photodynamic therapy of Barrett’s esophagus with 5-aminolaevulinic acid, Lasers Surg. Med. 31 (5) (2002) 299–304. [37] M.R. Stringer, C.J. Kelty, R. Ackroyd, S.B. Brown, Light dosimetry measurements during ALA-PDT of Barrett’s oesophagus, Photodiagnosis and Photodynamic Therapy 3 (1) (2006) 19–26. [38] U.C. Nzeako, J.A. Murray, An evaluation of the clinical implications of acid breakthrough in patients on proton pump inhibitor therapy, Aliment Pharmacol. Ther. 16 (7) (2002) 1309–1316. [39] J. Tack, G. Koek, I. Demedts, D. Sifrim, J. Janssens, Gastroesophageal reflux disease poorly responsive to single-dose proton pump inhibitors in patients without Barrett’s esophagus: acid reflux, bile reflux, or both? Am. J. Gastroenterol 99 (6) (2004) 981–988. [40] D. Milkes, L.B. Gerson, G. Triadafilopoulos, Complete elimination of reflux symptoms does not guarantee normalization of intraesophageal and intragastric pH in patients with gastroesophageal reflux disease (GERD), Am. J. Gastroenterol. 99 (6) (2004) 991–996. [41] P. Bytzer, Goals of therapy and guidelines for treatment success in symptomatic gastroesophageal reflux disease patients, Am. J. Gastroenterol. 98 (Suppl. 3) (2003) S31–S39. [42] S. Shay, R. Tutuian, D. Sifrim, M. Vela, J. Wise, N. Balaji, et al., Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers, Am. J. Gastroenterol. 99 (6) (2004) 1037–1043.
The effect of photodynamic therapy (PDT) on oesophageal motility and acid clearance in patients with Barrett’s oesophagus J. Globe b
a,*
, A. Smythe b, C.J. Kelty a, M.W.R. Reed a, N.J. Brown a, R. Ackroyd
b
a Academic Unit of Surgical Oncology, University of Sheffield, UK Department of Surgery, Academic Unit of Surgical Oncology, Floor K, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK
Received 27 February 2006; received in revised form 7 April 2006; accepted 7 April 2006 Available online 24 May 2006
Abstract Background: Barrett’s oesophagus is the major risk factor for oesophageal adenocarcinoma. It is proposed that long-term re-epithelialisation, which has been achieved following ablation using 5-aminolaevulinic acid (5-ALA) photodynamic therapy (PDT) may reduce the risk of malignant change. However, it is not known whether PDT modifies oesophageal motility. Aim: To assess oesophageal pH and motility before and after PDT ablation in treated and untreated areas of the oesophagus. Methods: Twelve patients (10 male) with Barrett’s oesophagus, median segment length 4 cm, were treated with PDT ablation. Twentyfour hours pH assessment and oesophageal manometry were performed before and 4–6 weeks after ablation. PDT was carried out using 635 nm red light, 4–6 h after administration of 30 mg/kg 5-ALA. Proximal (untreated) and distal (treated) oesophageal resting pressure, wave amplitude, percentage peristalsis and percentage study time oesophageal pH < 4, were assessed. Proton pump inhibitors (PPI) were administered throughout the study. Results: There were no significant differences in oesophageal motility in treated or untreated areas of the oesophagus after PDT compared to pre-treatment values. Patients who continued to experience oesophageal acid exposure required more treatments to achieve complete Barrett’s ablation. Conclusions: Oesophageal motility following ALA-PDT suggests a trend toward enhanced wave propagation however continued oesophageal acid exposure may affect PDT efficacy. 2006 Elsevier B.V. All rights reserved. Keywords: Barrett’s oesophagus; Oesophageal motility; Photodynamic therapy; ALA; Argon beam plasma coagulation
1. Introduction Oesophageal motility is often impaired in Barrett’s oesophagus, the level of impairment increasing with the Barrett’s segment length [1,2]. Controversy exists as to whether pre-existing disturbed motility leads to metaplasia, or if it occurs in response to prolonged mucosal injury. Poor oesophageal clearance increases oesophageal exposure to the presence of any noxious refluxate, therefore any treatment that reduces oesophageal motility and the
*
Corresponding author. Tel.: +44 114 2713223; fax: +44 114 2713314. E-mail address: J.Globe@sheffield.ac.uk (J. Globe).
1011-1344/$ - see front matter 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.jphotobiol.2006.04.001
efficacy of clearance mechanisms may have the potential to increase the risk of adenocarcinoma. Several different modalities are currently employed to treat Barrett’s oesophagus including proton pump inhibitor (PPI) therapy, anti-reflux surgery and mucosal ablation. Gastric acid suppression using a variety of PPI’s has been the predominant means of reducing both the volume and the acid content of reflux [3]. However, this fails to address the problem of duodeno-gastro-oesophageal reflux (DGOR), and the greatest complications have been seen to occur with concomitant acid and alkaline reflux [4]. Gastric acid suppression may reduce oesophageal clearance mechanisms resulting in prolonged oesophageal exposure to alkaline reflux [5], since the presence of acid within the
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oesophagus stimulates a number of receptors (mechanoreceptors, baroreceptors and chemoreceptors) to initiate both primary and secondary peristalsis to clear any refluxate [6– 8]. Neither gastric acid suppression nor anti-reflux surgery has been shown to achieve regression of the Barrett’s epithelium, or a reduction in the incidence of malignancy [9–11]. In contrast, mucosal ablation aims to reduce the risk of oesophageal adenocarcinoma by inducing squamous reepithelialisation. Several ablation therapies have been employed, including photodynamic therapy (PDT) and argon plasma coagulation (APC). Following randomised placebo controlled clinical trials using ALA-PDT [12] we have demonstrated long- term (5 years) mucosal re-epithelialisation in Barrett’s Oesophagus [13]. However, evidence of the effect of ablation therapy on oesophageal motility appears to be contradictory. The only PDT study published to date suggested that this therapy may be detrimental to oesophageal motility in some patients, possibly due to mucosal inflammation, scarring and fibrosis, or to systemic effects such as cytokine activation [14]. However, this study selected a mixed group of patients, including those with Barrett’s oesophagus and oesophageal carcinoma, and employed photofrin, a photosensitiser which accumulates both within the submucosa and muscularis mucosa, causing deeper tissue injury [15,16] when compared to ALA-PDT where the accumulation of the photosensitiser is restricted to the oesophageal mucosa [17,18]. A small study investigating the effects of APC on motility demonstrated that peristaltic amplitude may increase [19]. The choice of photosensitiser and the application of light during PDT can affect the depth of tissue injury due to photosensitiser accumulation and localisation, the wavelength required for activation (and therefore depth of treatment achieved) [20,21] and the degree of fibrosis that ensues; consequently, oesophageal contractility may also be affected by the same mechanism. It has been shown that mucosal injury resulting in oesophageal stenosis with the possible formation of stricture, may raise the oesophageal resting pressure [22]. Any reduction in the efficacy of oesophageal clearance mechanisms may prevent re-epithelialisation and promote further mucosal change. The primary aim of this study was to investigate the effects of ALA-PDT (30 mg/kg) on oesophageal motility and acid clearance in Barrett’s oesophagus, as there are no previously published studies. Motility was compared in treated (distal) and untreated (proximal) areas of the oesophagus, in addition to an assessment of 24 h pH, made prior to PDT treatment and after complete ablation was achieved, as identified by histological evaluation. 2. Materials and methods Research ethics committee approval was gained (South Sheffield Research Ethics Committee; Reference number 00/031) for this study. Informed written consent was obtained from 12 patients (10 males and 2 females, median
age 56 (range 51–81), all with biopsy proven metaplastic Barrett’s oesophagus recruited from a cohort undergoing endoscopic ablation in a clinical trial comparing PDT with APC [23]. The median Barrett’s segment length was 4 cm (range of 2–6 cm). All patients were administrated esomeprazole (Nexium, Astra Zeneca, UK) 40 mg daily throughout the trial. Prior to the study PPI therapy had been administered for at least 12 months and continued after the trial. Oesophageal manometry and 24-h pH studies were performed before the initial PDT treatment. PDT was repeated at 4–6 week intervals using 5-ALA 30 mg/kg and 635 nm red light until both macroscopic appearance and biopsies taken for histological assessment confirmed complete ablation. Assessment was carried out by a single experienced pathologist using modified Seattle criteria. Previous studies have shown that repeated treatments [23] with these parameters enhance Barrett’s regression when compared to a single PDT treatment [12]. The oesophageal manometry and 24-h pH study were repeated 4–6 weeks after complete ablation was achieved and an assessment was made of any differences in motility. 2.1. Oesophageal manometry A 9-lumen oesophageal catheter (Oakfield Instruments Ltd, Oxon, UK) was connected via transducers to water perfused manometry equipment (Albyn Medical, Dingwall, Ross-shire, Scotland – Phoenix system). Four radially spaced ports (90 apart) were positioned 5 cm from the catheter tip. Further ports were positioned longitudinally at 5 cm intervals along the catheter, which were also circumferentially orientated at 90 to adjacent ports. The catheter was introduced via the nares with the patient seated. Initially all of the ports were placed into the stomach. The manometry continued with the patient recumbent and the mid-axillary line level with the pressure transducers. The catheter was pulled back at 1 cm intervals until the four level ports nearest to the tip were placed within the lower oesophageal sphincter (LOS). The catheter was held in this position with micropore tape while 10 · 10 ml boluses of water were given orally at approximately 30 s intervals. Oesophageal function in both the untreated proximal oesophagus and the treated distal oesophagus was assessed by oesophageal manometry both before the start of treatment and after PDT ablation was achieved. Measurements were taken from the proximal untreated area, approximately 15 cm above the area of the LOS showing the highest pressure, and from the distal, treated area of the oesophagus, approximately 5 cm above the highest pressure point of the LOS. Following complete ablation, 4–6 weeks later, a second manometry evaluation was carried out. A standard oesophageal manometry protocol was used [24]. Mean mid-respiratory cycle pressure measurements were obtained (in cm H2O) and the following parameters measured: (1) Baseline lower oesophageal sphincter (LOS) pressure, (absolute pressure minus the gastric pressure); (2)
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length and location of the LOS; (3) diaphragm location seen on rapid deep inspiration; (4) mean peak contraction amplitude; (5) percentage peristalsis (percentage of wet swallows that generated peristaltic contractions; (6) resting (basal) oesophageal pressure, (a mid-respiratory measurement excluding any contractions). Waves were identified as peristaltic or non-peristaltic (simultaneous or absent). Peristaltic contractions with amplitudes <14 cm H2O were disregarded. After administration of a water bolus, a wet swallow was regarded as successful if it propagated an un-interrupted, peristaltic wave of contractions with amplitudes >30 cm H2O. 2.2. 24-h pH measurement The trans-nasally introduced pH electrode was secured with the tip positioned in the untreated area of the oesophagus, approximately 5 cm above the proximal border of the lower oesophageal sphincter. The location and length of the lower oesophageal sphincter had been established during the preceding manometry. Flexisoft 2 pH analysis software (Oakfield Instruments Ltd, Oxon, UK) was used to analyse the pH data. Meal times were excluded from the analysis. The number of acid reflux episodes were calculated and acid exposure (pH < 4) was determined as a percentage of the supine and upright periods. Patients continued PPI therapy (40 mg esomeprazole daily) during the 24 h oesophageal pH assessment. 2.3. PDT protocol The chosen photosensitiser was 5-aminolaevulinic acid (5-ALA), which preferentially accumulates in the mucosa [17,18]. ALA, a pro-drug, has no intrinsic photosensitising properties but is a metabolic precursor that is converted to protoporphyrin IX (PPIX), an endogenous photosensitiser in the haem biosynthetic pathway, [25]. An oral dose of 5ALA (DUSA Pharmaceuticals, Valhalla, NY, USA) was administered at 30 mg kg 1 4–6 h prior to laser endoscopy. We have previously determined that 30 mg kg 1 is as effective as 50 mg kg 1, produces similar amounts of PpIX and has less systemic toxicity [26]. Each patient underwent an endoscopy using an Olympus XQ240 Video endoscope (Olympus, Tokyo, Japan) with intravenous sedation, analgesia and anti-emetic (midazolam, fentanyl and ondansetron). To facilitate circumferential treatment of the affected area, a windowed balloon applicator (Wizard X-cell PDT balloon, Wilson Cook Medical, Winston-Salem, NC, USA) was used. A non-thermal monochromatic laser light was emitted from a cylindrical diffuser fibre (Pioneer Optics Company, Windsor Locks, CT, USA). The treatments employed 635 nm red laser light (Ceralas 635 nm 3 W diode laser, Biolitec AG, Germany) which was delivered at a fluence rate of 68 mW/cm2 and a total light dose of 85 J cm 2. The fluence rate delivered was calculated from the output power of the light source and the surface area
19
of the balloon. The parameters were also informed by previous studies [26,27]. Biopsies were taken at endoscopy 4 weeks after treatment. If residual Barrett’s mucosa was identified, further treatments were repeated at 4–6 weekly intervals until complete ablation was achieved, confirmed by histology. 2.4. Power calculation and statistics A sample size calculation was performed for paired data, using Sampsize Version 2.0 software. Long term clinical experience and unpublished data from our laboratory suggests that patients with Barrett’s oesophagus have P25% reduction in their mean contraction amplitude in the distal oesophagus compared to normal controls. Calculations were made based on a clinical significant difference of a 25% change in oesophageal pressure after treatment, with a power of 80% and a significance of 5%, which indicated that 11 patients were required. Statistical analysis was performed using the Wilcoxon signed rank test for paired, non-parametric data (Table 1). 3. Results 3.1. Manometry Oesophageal manometry was performed prior to the PDT treatment and compared to manometry after successful ablation was achieved (Table 1). Both proximal and distal areas of the oesophagus were included in the manometry. Patients in this study, pre- treatment, had essentially normal manometric values, except for reduced amplitude distal contractions, which is not unusual for patients with Barrett’s oesophagus [1]. The ALA-PDT did not induce any strictures and oesophageal resting presTable 1 Oesophageal motility in 12 Barrett’s patients, before and after 5-ALA PDT ablation Before PDT Untreated proximal area Oesophageal mean resting pressure (cm H2O) Contraction mean peak amplitude Peristalsis% Treated distal area Oesophageal mean resting pressure (cm H2O) Contraction mean peak amplitude Peristalsis% Lower oesophageal sphincter pressure (above gastric) Swallows Percentage successful swallows
After ablation
2 (4)a
1 (4)
NSb
50 (15) 73 (35)
54 (26) 78 (27)
NS
1 (5)
1 (4)
NS
71 (22) 76 (27) 19 (10)
60 (27) 81 (18) 19 (6)
NS NS NS
70% (30)
80% (20)
NS
NS = Not significant. a Results expressed as mean (standard deviation). b Statistical analysis performed using the Wilcoxon signed rank test for paired, non-parametric data. Statistical significance was assigned at the 5% level (p < 0.05).
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Table 2 Twenty-four hours pH in 12 Barrett’s patients before and after 5-ALA PDT ablation Untreated area
Acid exposure (% Study time pH < 4) Upright Acid exposure (% Study time pH < 4) Supine Reflux episodes Symptom index a
Before PDT
After ablation
2.2 (5)a 6.1 (12) 11 (18) 0
1.2 (2) 1.1 (2) 5 (6) 0
Results expressed as mean (standard deviation).
sures were not raised in either the treated or the untreated areas after PDT ablation. After PDT treatment there was a slight, although not statistically significant improvement in peristaltic wave propagation and in the number of successful swallows. The LOS pressures were within the normal range before and after PDT – see Table 1. 3.2. pH measurements There were no differences in total oesophageal acid exposure (expressed as a percentage of the total study time), or in the mean number of reflux events, after ALA PDT ablation compared to pre-treatment values, in either the upright or supine position (Table 2). Meal times were excluded from the pH analysis. Despite treatment with proton pump inhibitors, three of the twelve patients had breakthrough acid reflux resulting in an oesophageal pH below 4. The number of reflux episodes seen in these three patients were 62, 10, and 18, however, following successful ALA-PDT ablation. this was reduced to 6, 7 and 0, respectively. The total percentage oesophageal acid exposure time in these three individuals before PDT was 7.4%, 12.4%, and 12.9%. After ablation, the percentage acid exposure times were reduced to 0.9%, 4.4% and 0%, respectively. This study showed that for the entire group (n = 12) the median number of PDT treatments needed to achieve ablation was two. However the three individuals with persistent oesophageal acid exposure required a median number of four PDT treatments to achieve complete ablation – see Table 2. 4. Discussion This is the first study to show that ALA-PDT does not impair oesophageal motility indeed there may be a trend toward an increase in fully propagated waves and percentage of successful swallows following treatment, although not significant in this small study. The metaplastic response of the oesophageal mucosa to noxious stimuli is replacement of the stratified squamous epithelium with an intestinalised columnar epithelium, (Barrett’s oesophagus). Factors important to establishing a noxious free oesophageal environment are an effective gastro-oesophageal barrier and good oesophageal clear-
ance. Gastro-oesophageal reflux occurs physiologically; however, normally this is cleared rapidly from the oesophagus, due to stimulation of receptors within the oesophageal mucosa, which invoke peristalsis. In patients with reflux disease and/or Barrett’s oesophagus, this mechanism is impaired resulting in failure of acid clearance [6,28]. Successful squamous re-epithelialisation requires an acid free environment and so PPI’s are usually taken throughout ablation therapy [29]. The long-term (>5 years) mucosal re-epithelialisation of Barrett’s patients treated with ALA-PDT [13] observed in our previous studies could be due to maintenance of normal physiological motility [30]. To determine the effect of ALA-PDT ablation therapy on oesophageal function, oesophageal resting pressure, percentage peristalsis, contraction amplitude, lower oesophageal sphincter pressure and total oesophageal acid exposure expressed as a percentage of time (over 24 h) were quantified. Previous studies utilising oesophageal video fluoroscopy and manometry have demonstrated that contraction amplitudes <20 mm Hg may fail to propel a bolus adequately [31,32]. Any impairment in peristalsis or significant reduction in contraction amplitude may result in reduced oesophageal clearance, particularly whilst supine [33]. Patients in this study had essentially normal manometric measurements prior to PDT [30], however fully propagated waves and successful swallows were reduced. It is generally accepted that in the normal population during a standard pull through manometry P80% of wet swallows should generate peristaltic waves that are fully propagated (transmitted to the distal oesophagus). Results from this study showed that before ablation, only 70% contractions were transmitted to the distal oesophagus but after complete ablation this increased to lie within the normal range of 80%. This suggests that motility was not detrimentally affected by the PDT ablation. Infact there was a slight, but not statistically significant improvement in the percentage of propagated peristaltic contractions and number of successful swallows. Lower oesophageal sphincter pressures were unaltered by PDT ablation. Normal physiological manometric values were maintained following ALA PDT mucosal ablation. Any significant rise in either oesophageal resting pressures or lower oesophageal sphincter pressure could indicate the development of a stricture, which can be a complication of Barrett’s oesophagus or as a result of the ablation therapy [34]. In the current study, none of the patients developed a stricture and their oesophageal resting pressures and lower oesophageal sphincter pressures remained unchanged after treatment. Oesophageal acid exposure over a 24-h period was assessed as a percentage of study time. The patients all received PPI therapy throughout the entire study period, thus only patients who were either resistant to PPI’s, non-concordant with treatment, or receiving inadequate gastric acid suppression should exhibit any oesophageal acid exposure. This was the case for nine patients in the
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group, but in three patients, considerable oesophageal acid exposure was monitored despite PPI therapy prior to PDT treatment. An increase in acid exposure following treatment may indicate deterioration in acid clearance mechanisms or in the effectiveness of the gastro-oesophageal barrier. In the nine patients exhibiting normal oesophageal pH, this was maintained following treatment. However, in the three patients with continued oesophageal acid exposure, a marked reduction in acid was observed following successful ablation. These three patients required twice the median number of PDT sessions to achieve complete ablation, than the remainder that did not demonstrate any PPI breakthrough oesophageal acid exposure. This may suggest that oesophageal clearance mechanisms had improved slightly despite no statistically significant difference in oesophageal contraction amplitudes or percentage peristalsis. However due to the small patient numbers, firm conclusions cannot be made. The PDT treatment involved administration of 30 mg/ kg oral ALA 4 hours prior to light treatment, using, parameters determined from previous studies [26,27] demonstrating therapeutic efficacy. The issue of fluence rate and total fluence for optimal PDT response remains controversial and is influenced by a number of factors including the photosensitiser used and the geometry of the treatment area. One study using Photofrin-PDT demonstrated an increased incidence of stricture following treatment with a high light dose (115 J/cm [35]). A further study demonstrated that due to the light scattering in hollow organs there is an increase in the actual fluence rate at the oesophageal wall in vivo, suggesting that the delivery of high light fluence rates is not required [36]. This observation is supported by in vitro light dosimetry studies using an optical phantom, which demonstrated increased light fluences measured by an isotropic detector, when compared to the delivered fluence from the laser fibre [37]. In the current study, the number of PDT treatments required to achieve complete ablation, was not dependent on the total light dose received. Several studies have suggested that many GORD patients are resistant to PPI’s for a variety of reasons including failure of the proton pump, patient non-concordance and drug/drug interactions [38–41]. Currently, there is a lack of data regarding the prevalence of PPI resistance generally, as studies have tended to be carried out on select groups. Frequently patients with Barrett’s oesophagus are no longer symptomatic and are consequently reluctant to continue acid suppressive medication. In this study, all patients were asymptomatic, even during episodes of acid reflux. It is important that patients with Barrett’s oesophagus understand that oesophageal insensitivity often accompanies progression of their condition and that PPI therapy compliance is essential. Our study reinforces the importance of 24-h pH evaluation to establish adequate gastric acid suppression is occurring [42]. A suitable PPI, administered at an adequate dose to accomplish gastric acid suppression prior to ablation
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may be required to reduce the number of PDT sessions to achieve mucosal ablation. This has risk and financial implications. In conclusion, 5-ALA-PDT does not impair oesophageal motility and fewer ablative treatment sessions may be required to achieve complete ablation if adequate gastric acid suppression is achieved with PPI therapy. Acknowledgements The BUPA Foundation, Yorkshire Cancer Research and the Royal College of Surgeons of Edinburgh funded Mr Clive J. Kelty. CSUH Research Department also provided financial assistance. Authors would like to acknowledge Dr. T.J. Stephenson, Dept. of Histopathology, Royal Hallamshire Hospital, Sheffield, UK, for performing the histology assessments. References [1] P. Singh, R.H. Taylor, D.G. Colin-Jones, Esophageal motor dysfunction and acid exposure in reflux esophagitis are more severe if Barrett’s metaplasia is present, Am. J. Gastroenterol. 89 (3) (1994) 349–356. [2] H.J. Stein, S. Hoeft, T.R. DeMeester, Functional foregut abnormalities in Barrett’s esophagus, J. Thorac. Cardiovasc. Surg. 105 (1) (1993) 107–111. [3] J.E. Richter, Duodenogastric reflux-induced (alkaline) esophagitis, Curr. Treat. Options Gastroenterol. 7 (1) (2004) 53–58. [4] R.M. Bremner, P.F. Crookes, T.R. DeMeester, J.H. Peters, H.J. Stein, Concentration of refluxed acid and esophageal mucosal injury, Am. J. Surg. 164 (5) (1992) 522–526, discussion 526-7. [5] W. Meyer, F. Vollmar, W. Bar, Barrett-esophagus following total gastrectomy. A contribution to it’s pathogenesis, Endoscopy 11 (2) (1979) 121–126. [6] M.N. Schoeman, R.H. Holloway, Integrity and characteristics of secondary oesophageal peristalsis in patients with gastro-oesophageal reflux disease, Gut 36 (4) (1995) 499–504. [7] E. Corazziari, E. Materia, C. Pozzessere, F. Anzini, A. Torsoli, Intraluminal pH and oesophageal motility in patients with gastrooesophageal reflux, Digestion 35 (3) (1986) 151–157. [8] I. Bontempo, L. Piretta, E. Corazziari, F. Michetti, F. Anzini, A. Torsoli, Effects of intraluminal acidification on oesophageal motor activity, Gut 35 (7) (1994) 884–890. [9] J.A. Jankowski, M. Anderson, Review article: management of oesophageal adenocarcinoma – control of acid, bile and inflammation in intervention strategies for Barrett’s oesophagus, Aliment Pharmacol. Ther. 20 (Suppl. 5) (2004) 71–80, discussion 95-6. [10] S. Haag, S. Nandurkar, N.J. Talley, Regression of Barrett’s esophagus: the role of acid suppression, surgery, and ablative methods, Gastrointest. Endosc. 50 (2) (1999) 229–240. [11] N.A. Shepherd, Barrett’s oesophagus and proton pump inhibitors: a pathological perspective, Gut 46 (2) (2000) 147–149. [12] R. Ackroyd, N.J. Brown, M.F. Davis, T.J. Stephenson, S.L. Marcus, C.J. Stoddard, A.G. Johnson, M.W. Reed, Photodynamic therapy for dysplastic Barrett’s oesophagus: a prospective, double blind, randomised, placebo controlled trial, Gut 47 (5) (2000) 612–617. [13] R. Ackroyd, C.J. Kelty, N.J. Brown, T.J. Stephenson, C.J. Stoddard, M.W. Reed, Eradication of dysplastic Barrett’s oesophagus using photodynamic therapy: long-term follow-up, Endoscopy 35 (6) (2003) 496–501. [14] N. Malhi-Chowla, H.C. Wolfsen, K.R. DeVault, Esophageal dysmotility in patients undergoing photodynamic therapy, Mayo Clin. Proc. 76 (10) (2001) 987–989.
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