ALA PDT for high grade dysplasia in Barrett s oesophagus review of a decade s experience

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1 ALA PDT for high grade dysplasia in Barrett s oesophagus review of a decade s experience Stephen G Bown, Gary D Mackenzie, Jason M Dunn, Sally M Thorpe, Laurence B Lovat National Medical Laser Centre, Division of Surgery and Interventional Science, University College London, 1 st Floor Charles Bell House, Riding House Street, London W1W 7EJ, UK and Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, 235 Euston Road, London NW1 2BU, UK ABSTRACT We have been investigating PDT with 5 aminolaevulinic acid (ALA) for the treatment of high grade dysplasia (HGD) in Barrett s oesophagus (BO) for over a decade. This drug has inherent advantages over porfimer sodium (Photofrin), the current approved photosensitiser in the UK and USA, which causes strictures in 18-50% and light sensitivity for up to three months. ALA has a lower rate of oesophageal strictures due to its preferential activity in the mucosa, sparing the underlying muscle, and patients are only light sensitive for 1-2 days. Within a randomised controlled trial, we demonstrated that an ALA dose of 60mg/kg activated by 1000J/cm red laser light is the most effective. Using these values we achieved complete reversal of HGD at 1 year in 89% of 27 patients. A randomised controlled trial of ALA vs porfimer sodium PDT for HGD is currently under way with end points of efficacy and safety. 50 of 66 patients have been recruited. Preliminary data suggest ALA PDT is safer with a trend to higher efficacy. Late relapse can occur in 20% of patients. New prognostic markers, in particular aneuploidy, are helping us to identify and target patients at risk of late relapse. Furthermore optical biopsy techniques such as elastic scattering spectroscopy (ESS) may allow detection of nuclear abnormalities in vivo and enable us to target areas of interest whilst reducing sampling error. PDT faces new challenges for the treatment of HGD in BO, with the recent introduction of balloon based radiofrequency ablation. This technique appears simpler and as effective as PDT, but follow up is currently short and long term safety data is lacking. In our experience ALA PDT is currently the most effective minimally invasive treatment for HGD in BO. This work was undertaken at UCLH/UCL who received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. Keywords: Barrett s oesophagus, dysplasia, photodynamic therapy, mucosal ablation. Tel: Fax: s.bown@ucl.ac.uk website: ucl.ac.uk/surgery/nmlc Photodynamic Therapy: Back to the Future, edited by David H. Kessel, Proc. of SPIE Vol. 7380, SPIE CCC code: /09/$18 doi: / Proc. of SPIE Vol

2 BACKGROUND Oesophageal cancer is the fifth commonest cause of cancer death in the United Kingdom and Northern Europe. The majority of cases are now adenocarcinomas, most of which arise in Barrett s oesophagus (BO), which arises in about 10% of patients with significant gastro-oesophageal reflux. 1 Over many years, up to 15% of this group develop dysplasia, which may progress to invasive cancer. 2 The clinical challenge is to identify and treat patients with dysplasia before invasive disease develops. 3 The optimal treatment strategy for managing high-grade dysplasia (HGD) in BO is unclear. Oesophagectomy is conventionally considered as first-line therapy but even in good hands has up to 5% mortality and a 40% morbidity. 4 Many patients are elderly with co-morbid disease and are considered unfit to undergo such a major procedure. Minimally invasive approaches for disease limited to the mucosa are a much more attractive option. Mucosal ablation can be achieved with endoscopic mucosal resection (EMR), 5 radiofrequency ablation 6 and photodynamic therapy. EMR is most effective when abnormalities are visible. However, HGD and intramucosal carcinoma may be patchy and occult within the Barrett s segment. Circumferential EMR may be successful but is technically demanding and can result in complications like oesophageal strictures. 7 Photodynamic therapy (PDT) is the best-studied method for uniform, comprehensive mucosal ablation. It is a nonthermal, photochemical reaction. PDT has the advantage that light can be evenly and circumferentially distributed over the whole treatment area. PDT also appears to spare collagen, with the potential to preserve structural integrity and reduce the risk of perforation. 8 The first-generation photosensitiser, Photofrin (porfimer sodium), is licensed in the USA and Europe for the treatment of dysplasia in BO and two recent cost effectiveness analyses have suggested that PDT provides the longest quality adjusted life expectancy. 9 A randomised trial for HGD in Barrett s oesophagus comparing Photofrin PDT to medical treatment alone (omeprazole) demonstrated a 50% reduction in the incidence of cancer at 2 year follow up. Photofrin PDT, however, causes oesophageal strictures in up to one third of patients and significant skin photosensitivity may persist for 2-3 months after treatment, 10 which limit its acceptability. ALA The alternative photosensitizing agent, ALA (5-aminolaevulinic acid) is converted in vivo into its photoactive metabolite, protoporphyrin IX (PPIX). This accumulates more in the mucosa than in underlying muscle in hollow organs like the oesophagus. This markedly reduces the risk of producing strictures. Further, PPIX is eliminated from the body by 36 hours, so there are no problems with prolonged skin photosensitivity. ALA is not perfect. At doses higher than 60mg/kg there is a risk of liver toxicity and minor abnormalities of liver function are seen even at this dose, although they resolve spontaneously. If patients are not adequately hydrated prior to ALA administration, they can become hypotensive and nausea often occurs, but it is rare for any of these problems or skin photosensitivity to last more than 24 hours after drug administration. All reported studies of ALA-PDT in the oesophagus use some sort of centering device for uniform illumination of the oesophageal mucosa, although the diameter of the device used is not always specified and does differs between reports. In discussion of the light doses used, it is essential to express the light dose in the same way for all studies. The treated surface area changes with the size of the centring balloon although the total number of cells treated is unchanged. This creates difficulties when defining the light dose as J/cm 2 of mucosal surface. We suggest, therefore that it is more appropriate to describe the light dose per centimetre length of treated oesophagus (J/cm) and all doses in this paper are expressed in these terms. Where the dose has been reported in J/cm 2 without defining the diameter of the device used, we have made a best estimate of the diameter, based on personal communications with authors. The first important report of ALA-PDT for dysplasia in Barrett s gave most encouraging results. 11 However, there have been a wide variety of regimens suggested with highly variable results. The most impressive case series of 35 patients treated for HGD with 60mg/kg ALA activated by a red light dose of 850J/cm reported an 89% (31/35) eradiation rate without recurrence at 3 years follow-up. 12 This must be compared to the disappointing results of a different study of Proc. of SPIE Vol

3 ALA-PDT (40mg/kg ALA activated by 785J/cm of light) reporting only a 55% (11/20) long term eradication rate for HGD when combined with EMR. 13 The PDT regimens used to treat all grades of dysplasia vary in the light dose, the oral dose of ALA (30-60mg/kg) and the wavelength of light used (red or green). The light dose used has been as little as 350 J/cm through 550 J/cm and up to 1000 J/cm 2. 14,15,16 It is hardly surprising that very different success rates have been reported. Furthermore, none of these studies have compared the relative efficacy of different doses of light in the same cohort of patients holding other parameters constant. If any new treatment is to be compared with conventional therapy, it is essential to optimize the way of delivering the new treatment before performing any comparative studies. With such a variation in the published ALA results, it was clear that studies were required to optimize the key variables, which is what we did. One of the main problems optimizing PDT is that there are so many variables. Trying to optimize all of them in randomized studies would require an excessively large number of patients, so compromises were made on numbers, but the overall picture that emerges is clear. CLINICAL TRIALS TO OPTIMIZE ALA-PDT The variables studied were the dose of ALA, the colour of the activating light and the light dose. 17,18 It is of historical interest that comparable studies were not performed for porfimer sodium until recently, in an attempt to reduce the incidence of oesophageal strictures. 19 At the start of these studies, all patients were given ALA as a single dose of 30mg/kg dissolved in water, 4 hours before light delivery. This was later increased to 60mg/kg, given as 3 doses of 20mg/kg, given an hour apart, with light delivery 3 hours after the last dose. Endoscopy was performed under conscious sedation with midazolam (2-10mg) and pethidine (25-50mg). We initially used 25mm Wizard X-Cell balloons for light delivery (Wilson-Cook, USA) inflated with 35 ml water, but later replaced these by flexible silicone bolsters (diameter 16mm) designed and manufactured in our department of medical physics. 20 The delivery device was passed over a guide-wire into the oesophagus to the required distance. The guide wire was removed and a cylindrical diffuser fiber (Biolitec, Germany) matching the length of the delivery device was passed through the guide-wire channel so that it lay centered within the device at the level of the treatment area. Up to 7cm of Barrett s could be treated with a single fibre; if the Barrett s segment was longer then treatments overlapping by 0.5cm were performed. For comparisons between different activation wavelengths, we used green light (512nm) from a Copper Vapour Laser (Oxford Lasers, Oxford, UK) and red light (635nm) from three Diode Lasers (Diomed, Cambridge, UK), focused into a single optical fibre. The light dose was the same for both wavelengths in the red v green study. Red v Green 17 RESULTS The red v green results are summarized in Table 1, with Kaplan Meier curves showing the time to relapse to HGD or cancer in Figure 1 and the reduction in length of Barrett s segment in Table 2. We started using the low dose of ALA, 30mg/kg, with both red and green light. An interim analysis was performed after 16 patients had been randomised between red and green. Only 4 had successful eradication of HGD (25%), so the study was paused. After discussion with the ethics committee, the trial was restarted using ALA at 60mg/kg. Despite the better results from other groups using green light, we felt that these results were too poor to justify continuing with the low dose. Proc. of SPIE Vol

4 PDT Regimen n Developed Cancer Relapsed to HGD/Cancer Success Rate Log Rank p Value Fisher s Exact Test p Value 60mg/kg ALA Red % NA Comparator 60mg/kg ALA Green 5 1 (20%) 4 20% p=0.008 P= mg/kg ALA Red 8 1 (12%) 5 37% p=0.005 p= mg/kg ALA Green 8 4 (50%) 7 12% p<0.001 p=0.005 Table 1: Univariate analysis of RCT for eradication of HGD using ALA-PDT Figure 1: Red light v Green light. Time without relapse to HGD (left) or cancer (right) Laser Light Reduction in Visual Mapping After PDT Reduction in Histological Mapping After PDT Red 59% 46% Green 7% -10% P Value Table 2: Reduction in extent of Barrett s segment after PDT Effect of light dose 18 The results are shown in Figure 2. The highest light dose was significantly better than low and medium light dose for the eradication of HGD (Log rank test, p<0.01). There is a clear correlation between the light dose delivered and the treatment response (Figure 2). Seven out of ten patients (70%) treated with the highest light dose (1000J/cm) compared to 2/9 (22%) receiving medium light dose (750J/cm) and 0/5 (0%) receiving low light dose (500J/cm) had successful long-term eradication of HGD. Proc. of SPIE Vol

5 Figure 2: Clearance of HGD comparing high and low doses of ALA and red light DISCUSSION Two studies treating low-grade dysplasia (LGD) reported excellent eradication rates using green light at much lower light (264J/cm) and drug (30mg/kg) doses than in our study. 21,22 The extinction coefficient of PPIX has been shown to be higher at 512nm than at 635nm and so for equal light doses green might indeed be expected to perform better, although green light is more strongly absorbed by blood and so its effect is more superficial. Thus, green light might have been expected to be effective in the eradication of HGD. Our study shows exactly the opposite, with very poor results using green light and is the only one to undertake a randomized comparison between red and green, so should carry more weight than a study only using one colour. Nevertheless, it is not clear why there should be such a dramatic difference between the effects on LGD and HGD, but we now consider that HGD should only be treated with red light. Most published trials using ALA and red laser light to treat HGD have used a dose of 60mg/kg, with success rates of 12, 14, 23 between %. Two studies using lower doses had poor response rates; 20% using 30mg/kg ALA (15) and 55% using 40mg/kg. 13 Our study provides convincing supporting data that the higher dose of ALA is more effective. The incidence of side effects is slightly higher with 60mg/kg, but this would appear acceptable for the greater efficacy. Our results confirm the need for a light dose of around 1000J/cm. Other publications have shown good results with a light dose of about 850J/cm, 12 but our data showed much less satisfactory results at 750J/cm and little useful effect at 500J/cm. In addition to the colour of the light and the doses of drug and light, several other factors may influence the efficacy of ALA PDT in the oesophagus. From experimental studies, it is known that the fluence rate (the speed at which light is delivered) influences the effect a particular light dose is more effective if given over a longer time period ( 24 ). The light fluence rate in the oesophageal lumen is often higher than the rate delivered from the fibre due to multiple reflections from the oesophageal wall. Of course, this cannot increase the total light energy available, but it can change Proc. of SPIE Vol

6 the distribution of light within the wall of the oesophagus. If reflection is high, the average angle at which light enters the mucosa is close to tangential, so the path length of light within the mucosa is longer than if reflection is low, when the incident angle is closer to perpendicular to the mucosal surface. Bearing in mind that the penetration depth of the light used for ALA-PDT (635nm) is 2-3 mm and the mucosal thickness is only of the order of 0.5mm, the effect of internal reflections in the lumen of the oesophagus can be quite dramatic. Considerably more light will be absorbed in the mucosa (where the biological effect is wanted) when there is more reflection within the oesophageal lumen and not in the underlying muscle (where it is important to minimise any biological effect). To assess this accurately, it may be necessary to monitor the light fluence in the lumen to allow for this effect in deciding on the appropriate total light dose to deliver. 25 In addition, distending the oesophagus will make the mucosa thinner, which will also change the percentage of the delivered light that is absorbed in the mucosa rather than in deeper layers of the oesophageal wall, so the optimum dose may depend on the diameter of the light delivery device used Volume of Necrosis (mm 3 ) Continuous F20/80 Treatment Regime Volume of Necrosis (mm 3 ) ALA + ALA only CP94 Treatment Regime Figure 3: Enhancement of extent of PDT necrosis in normal rat colon 27 Left: light fractionation compared with continuous illumination Right: ALA alone compared with ALA plus the iron chelator CP94 Two other factors have been shown in experimental studies to enhance PDT. Fractionating the light (turning off the light for a period of a couple of minutes at a strategic point during illumination) can increase the extent of necrosis by a factor of up to Also, administering an iron chelator can slow down the conversion of PPIX to haem, so increasing the tissue level of PPIX. This can also enhance the PDT effect by a factor of up to about 3 and as the mechanism is quite different from that of fractionation, the 2 effects can be additive. 27 These effects are shown in Figure 3. Thus it is clear that dosimetry for oesophageal PDT is complex, much of which is beyond the scope of this paper. The safety of any new technique is of crucial importance. No patient in the studies described here has developed an oesophageal stricture or phototoxicity and none have developed advanced oesophageal cancer (all staged T1N0). There was one aspiration pneumonia and we are now careful to treat all patients semi-recumbent rather than completely flat. After our initial experience of profound hypotension in 2 patients, all subsequent patients were well hydrated prior to ALA administration and remained in hospital for at least 24 hours after treatment. We ensured all patients were able to eat and drink prior to discharge and no further problems occurred. Two other groups who recently presented their initial 15, 28 experience with ALA PDT reported one fatality each. Both patients were treated as outpatient day cases. The cause of death was aspiration pneumonitis in one and not determined in the other, but was within a day of treatment. This death may also have been related to inadequately treated hypotension or aspiration pneumonia. Proc. of SPIE Vol

7 In conclusion, ALA-PDT is a useful approach to treating HGD in Barrett s oesophagus that avoids the main problems associated with porfimer sodium PDT. A high light dose is required (at least 1000J/cm) and it is essential to treat the full length of the Barrett s segment adequately. Careful follow-up is needed to ensure that failures and relapses are detected early. A randomized study comparing PDT with ALA and porfimer sodium is currently under way. 29 Radiofrequency ablation 6 is receiving a lot of attention as a technique for endoscopic ablation of dysplasia in Barrett s oesophagus which does not require a drug, although little long term follow up data is yet available. It would now be appropriate to undertake a study comparing PDT with radiofrequency ablation. REFERENCES [1] Cameron, A.J., Ott, B.J., and Payne, W.S. The incidence of adenocarcinoma in columnar-lined (Barrett's) esophagus, N Engl J Med 313(14), (1985). [2] Cameron, A.J. and Carpenter, H.A. Barrett's esophagus, high-grade dysplasia, and early adenocarcinoma: a pathological study, Am J Gastroenterol 92(4), (1997). [3] Reid, B.J., Levine, D.S., Longton, G., et al. Predictors of progression to cancer in Barrett's esophagus: baseline histology and flow cytometry identify low- and high-risk patient subsets, Am J Gastroenterol 95(7), (2000). [4] Tseng, E.E., Wu, T.T., Yeo, C.J., et al. Barrett's esophagus with high grade dysplasia: surgical results and long-term outcome an update, J Gastrointest Surg 7(2), (2003). [5] Ell, C., May, A., Gossner, L., et al. Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett's esophagus, Gastroenterology 118(4), 670-7, [6] Sharma, V.K., Wang, K.K., Overholt, B.F., et al. Balloon-based, circumferential, endoscopic radiofrequency ablation of Barrett's esophagus: 1-year follow-up of 100 patients, Gastrointest Endosc 65(2), , [7] Satodate, H., Inoue, H., Fukami, N., et al. Squamous reepithelialization after circumferential endoscopic mucosal resection of superficial carcinoma arising in Barrett's esophagus, Endoscopy 36(10), (2004). [8] Barr, H., Tralau, C.J,, Boulos, P.B., et al. The contrasting mechanisms of colonic collagen damage between photodynamic therapy and thermal-injury, Photochem Photobiol 46(5), (1987). [9] Shaheen, N.J., Inadomi, J.M., Overholt, B.F., et al. What is the best management strategy for high grade dysplasia in Barrett's oesophagus? A cost effectiveness analysis, Gut 53(12), (2004). [10] Overholt, B.F., Lightdale, C.J., Wang, K.K., et al. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international, partially blinded, randomized phase III trial, Gastrointest Endosc 62(4), (2005). [11] Gossner, L., Stolte, M., Sroka, R., et al. Photodynamic ablation of high-grade dysplasia and early cancer in Barrett's esophagus by means of 5-aminolevulinic acid, Gastroenterology 114(3), (1998). [12] Pech, O., Gossner, L., May, A., et al. Long-term results of photodynamic therapy with 5-aminolevulinic acid for superficial Barrett's cancer and high-grade intraepithelial neoplasia, Gastrointest Endosc 62(1), (2005). Proc. of SPIE Vol

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9 [28] Haringsma, J., Siersema, P.D. and Kuipers, E.J. Endoscopic ablation of Barrett's neoplasia. Rotterdam results, Gastrointest Endosc 59(5), AB252 (2004). [29] Mackenzie, G.D., Dunn, J.M., Novelli, M.R., et al. Preliminary results of a randomised controlled trial into the safety and efficacy of ala versus photofrin photodynamic therapy for high grade dysplasia in Barrett's oesophagus, Gut 57, A14 (2008). Proc. of SPIE Vol