Photodiagnosis and Photodynamic Therapy (2004) 1, 137—143
5-Aminolaevulinic acid compared to polyhematoporphyrin photosensitization for photodynamic therapy of malignant bronchial and esophageal stenosis: clinical experience Veronika Matzia, Alfred Maiera, Oliver Sankina, J¨ org Lindenmanna, uttner MDa,∗ Peter Rehakb, Freyja M. Smolle-J¨ a
Division of Thoracic and Hyperbaric Surgery, Department of Surgery, University of Medicine, Auenbruggerplatz 29, A-8036 Graz, Austria b Division of Biomedical Engineering and Computing, University of Medicine, Graz, Austria KEYWORDS 5-Aminolaevulinic acid; Polyhematoporphyrin and malignant bronchial and esophageal stenosis
∗
Summary Background and objective: Polyhematoporphyrins (PhP) as sensitizers for photodynamic therapy (PDT) in malignant bronchial and esophageal stenosis carry the risk of prolonged photosensitivity of the skin. New line sensitizers such as 5-aminolaevulinic acid (ALA) with low rates of skin phototoxicity appear to be promising alternatives. The aim of this study was to evaluate the efficacy of ALA compared to PhP for PDT regarding phototoxicity of the skin, reduction of tumour stenosis and tumour length and Karnofsky performance status. Patients and methods: After diagnostic work-up, photosensitization was done in 38 patients with ALA (60 mg/kg body weight, oral, 6—8 h prior to PDT) and in 51 patients with PhP (2 mg/kg body weight, i.v., 48 h before PDT). The light dose was calculated as 300 J/cm fibre tip. Light at 630 nm was applied using a pumped dye laser. In both groups, additional hyperbaric oxygenation was applied at a level of 2 bar absolute pressure. Results: Improvement regarding stenosis diameter, tumour length and Karnofsky performance status could be obtained in both treatment arms with a significant difference in favour of the PhP-group, P = 0.00073; 0.000014, and 0.00015, respectively. No sunburn or other major treatment related complications occurred in either treatment arms. Conclusion: Photosensitization with PhP compared to ALA seems to be more effective in PDT of malignant bronchial and esophageal stenosis. © 2004 Elsevier B.V. All rights reserved.
Corresponding author. Tel.: +43 316 385 3302; fax: +43 316 385 4679. E-mail address: [email protected] (F.M. Smolle-J¨ uttner)
1572-1000/$ — see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(04)00040-7
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Introduction Photodynamic therapy (PDT) has been shown to be a promising non-thermic laser technique, which produces localized tissue necrosis induced by light following administration of a photosensitizing drug. The drug is activated by illumination at a specific wavelength matching its absorption spectrum. Compared to thermic techniques, e.g. Nd:YAG-laser or radiotherapy, which usually affect all parts of the wall, damaging collagen fibres and smooth muscle, PDT is more selective, sparing the collagen fibres and hence enabling healing by regeneration [1]. However, the present status of PDT is far from being ideal. In addition to problems with oxygen supply during PDT and precise light dosimetry, there are still difficulties in finding the ideal sensitizer. Clinically, the most widely used sensitizers are hematoporphyrin derivatives. In spite of promising results in the treatment of malignant esophageal and tracheo-bronchial stenosis [2—9] the use of this type of sensitizer is associated with undesirable side effects, such as prolonged cutaneous photosensitivity persisting up to 3 months [10]. New sensitizers such as 5-aminolaevulinic acid (ALA), which combine acceptably low rates of skin phototoxicity and clinically useful tumour tissue specificity, appear to be promising alternatives [11,12]. 5-ALA is a naturally occurring precursor for the heme biosynthetic pathway, which is intracellularly converted into the active compound, protoporphyrine IX (Pp IX). Under normal conditions, the enzyme ALAsynthetase is regulated by a negative feedback control mechanism, which responds to changes in heme concentration. When exposed to a large amount of exogenous ALA, the biosynthetic pathway is overloaded, resulting in the accumulation of certain porphyrin intermediates, especially Pp IX [11]. In more recent studies [8—12], it was shown that tumour tissue can be destroyed by ALA-induced Pp IX photodynamic therapy. A drawback of ALA, however, is the fact that the depth of therapy-induced necrosis has been reported to be less than the one achieved by PhP [9,11]. The aim of this clinical study was to evaluate the use of 5-ALA compared to PhP in photodynamic therapy of malignant esophageal and tracheo-bronchial stenosis. Phototoxicity of the skin, reduction of tumour stenosis, and tumour length as well as an improvement of Karnofsky performance status were considered as main outcome variables. Improvement of dysphagia and dyspnea, as well as reduction of hemoptysis and poststenotic pneumonia were considered as second objectives. Since previous studies [14,15] have shown significant enhancement of the oxygen-dependent PDT-
V. Matzi et al. photoreaction by administration of hyperbaric oxygen (HBO), we used adjunctive HBO during PDT in all patients.
Patients and methods One hundred and one patients with malignant esophageal or tracheo-bronchial stenosis not eligible for resection treatment because of poor performance status, functional and/or anatomical inoperability, and/or refusal of surgery were randomized. Because of inconstant availability of either photosensitzer during the first half of the study period in Austria, 12 patients had to be secondarily excluded. Eighty-nine patients entered the study. The protocol was approved by the institutional ethical committee of the medical faculty at the University of Graz. Informed written consent was obtained from each patient. In 38 patients, photosensitization was done with ALA and in 51 patients, Photosan-3® (Seehof Laboratory, Wesselburenkoog, Germany; Fig. 1), a mixture of porphyrin oligomers, was administered. The patients were selected into two treatment arms independent of the stage of disease, histology, age, sex, tumour stenosis, tumour length and Karnofsky performance status (KPS). Diagnostic work-up and clinical staging were done by esophagoscopy, bronchoscopy, computed tomography scans of the chest, abdominal ultrasonography and bone scan. Functional inoperability was confirmed by electrocardiogram, spiroergometry, blood gas analysis and cardiac ultrasonography. In the ALA-group, the photosensitizer (5aminolaevulinic acid, Medac Research® Wedel, Germany) was orally administered at a dose of 60 mg/kg body weight, 6—8 h prior to PDT. Thirtyone patients were male and seven were female (mean age: 64 years). Squamous cell carcinoma was evident in 22 and adenocarcinoma in 16 cases. By clinical TNM staging, 12 patients were stage III and 26 in stage IV. The Karnofsky performance status was at a mean level of 78 (range: 60—90). In cases with tracheo-bronchial lesions the mean stenosis was 79% of the normal luminal diameter (range: 50—90%). All patients complained about dyspnea as well as hemoptysis. Nine patients showed additional radiological and clinical signs of poststenotic pneumonia. In patients with malignant esophageal lesions the mean stenosis diameter was 8.4 mm (range: 7—14 mm). The mean tumour length at the time of admission was 6.8 cm (range: 5—10 cm). At the time of admission, all patients complained about dysphagia of solid food (level 1), semisolid diet (level 2) and liquids (level 3) within the past
5-Aminolaevulinic acid compared to polyhematoporphyrin photosensitization 3 months. Nutrition was possible using semisolid and/or liquid food. Skin protection was done by a camouflage (Covermark® , Milan, Italy) for 24 h after photosensitization. In the PhP-group, the photosensitizer (Photosan3® , Seehof Laboratory, Wesselburenkoog, Germany) was administered intravenously at a dosage of 2 mg/kg body weight, 48 h prior to PDT. Thirtyseven patients were male and 14 were female (mean age: 66 years). Squamous cell carcinoma was evident in 28 and adenocarcinoma in 23 cases. By clinical TNM staging, 31 patients were stage III and 20 stage IV. The Karnofsky performance status was at a mean level of 70 (range: 60—80). In case of malignant tracheo-bronchial lesions the mean stenosis was 50% of the normal luminal diameter (range: 20—95%). All patients complained about dyspnea as well as hemoptysis. Thirteen patients showed additional radiological and clinical signs of poststenotic pneumonia. In patients with malignant esophageal lesions the mean stenosis diameter was 8.4 mm (range: 4—12 mm). The mean tumour length at the time of admission was 6.3 cm (range: 4—10 cm). All patients complaint about dysphagia level 1—3 and six patients complained of aphagia (level 4) and were not able to handle their saliva and parenteral nutrition before PDT became necessary. Skin protection was done by using a commercially available sun-blocker (Solgard; SP FARMA, Portugal) for 12 weeks. In case of severe tumour stenosis, PDT was carried out by using a fibre with a 2-cm tip radial light diffusing cylinder (Photo Dynamic Therapy® HgesmbH, 1190 Vienna, Austria), which was inserted through the biopsy channel of the endoscope. In case of moderate tumour stenosis, a 2 cm balloon applicator system (Photo Dynamic Therapy® HgesmbH) was used to perform a homogenous light distribution. During treatment, the radial light diffusing cylinder and/or balloon applicator system was positioned closely to the tumour surface. The light dose was calculated as 300 J/cm fibre tip [13]. Light at 630 nm was applied using a diode laser system [Ceramoptec® , Bonn, Germany]. Wavelength and light dose at the tip of the light diffuser were controlled before and after PDT. In both groups additional hyperbaric oxygenation, as reported earlier [14,15], at a level of 2 ATA in the walk-in hyperbaric chamber at the University Hospital of Graz (Waagner Biro® AG, Graz, Austria) was done. Oxygen was applied over a mechanical ventilator (Servo 900 C, Siemens, Erlangen, Germany). Before hyperbaric oxygenation, all patients had an ear, nose and throat check-up.
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Each treatment was performed under shortterm intravenous anaesthesia (Propofol 1% AstraZeneca® , Vienna, Austria) with endotracheal intubation. Monitoring included electrocardiogram, noninvasive continuous blood pressure control, tcp02 (TCM® , Radiometer Medical A/S, Copenhagen, Denmark).
Follow-up Follow-up investigations were scheduled at 1 and 4 weeks after combined PDT/HBO. The effects on tumour stenosis were assessed by endoscopy, chest X-ray, spirometry and subjective relief of dyspnea, hemoptysis and dysphagia as well as clinical signs of poststenotic pneumonia and laboratory parameters corresponding to inflammatory processes (WBC, CRP and fibrinogen). The Karnofsky performance status was recorded at each follow-up. The effect on tumour stenosis was estimated by comparing the pre- and postinterventional increase of luminal diameter measured at the point of maximum constriction. All luminal diameters were estimated by the easy passage of graduated Bronchoscopes of known diameter (3.2, 5, 6 and 7 mm) and/or easy passage of ballon catheters of known diameter (8—23 mm). The minimum lumen of the treated region was recorded at each endoscopy.
Additional treatment At least 4 weeks after combined PDT/HBO all patients were considered for further treatment, i.e. high-dose rate (HDR) brachyradiotherapy, external beam irradiation and/or chemotherapy, depending on the oncological situation and the patients consent. In the ALA-group, all patients received HDR brachyradiotherapy at a total dose of 15 Gy (5 Gy/per session). In 12 patients the treatment was completed by external beam irradiation (EBR) using the multiple field technique to administer a total dose of 40 Gy. Eight patients received three cycles of chemotherapy. In the PhP-group, all patients received HDR brachyradiotherapy (15 Gy). In 31 patients, radiotherapy was completed by EBR (40 Gy). Twenty-one patients received three cycles of chemotherapy.
Statistical analysis Statistical analysis was performed by Chi-square test, Fisher’s exact test and analysis of variance (ANOVA). Survival distribution was determined with the Kaplan—Meier survival table.
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Results Statistical analysis of qualitative variables showed no significant difference before entering the treatment schedule between both treatment arms as to sex (P = 0.71; Fisher’s exact test), localization (P = 0.80; Chi-square test), histology (P = 0.20; Chi-square test), and UICC-stage (P = 0.066; Kruskal—Wallis test). Karnofsky performance status (P = 0.0008; Kruskal—Wallis test) and stenosis diameter (P = 0.0001; Kruskal—Wallis test) showed a significant difference with a better KPS and a less degree of stenosis for the ALA-group before entering the treatment schedule However, for statistical analysis the difference from baseline to 4-week follow-up for each group was done.
Primary objectives: (Tab 1) In the ALA-group, the Karnofsky performance status showed little improvement. The mean value changed from baseline 78 to 4-week follow-up 79. In only five patients an improvement of 10% could be documented. The stenosis diameter in tracheobronchial lesions dropped from a mean value of 79% at baseline to 63%. In patients with esophageal lesions the mean decrease in diameter of stenosis was 2.8 mm at 4-week follow-up. The mean reduction of tumour length in esophageal lesions was 1.2 cm. In the PhP-group, the Karnofsky performance status improved by 10% in 26 patients and by 20% in 11 patients. In 14 patients no improvement was found. The mean value changed from 70 at baseline to 79 at 4-week follow-up. Statistical analysis showed a significant difference (P = 0.00015; ANOVA) in favour of the PhP-group. In tracheo-bronchial lesions the stenosis diameter dropped from a mean value of 50% at baseline to 19% and in patients with esophageal lesions the mean decrease of stenosis was 6.0 mm at 4-week follow-up. Statistical analysis showed a significant difference (P = 0.00073; ANOVA) in favour of the PhP-group. In esophageal stenosis the mean reduction of tumour length was 2.7 cm in the PhP-group, comparing favourably with the ALA-patients (P = 0.000014; Mann—Whitney U-test).
Secondary objectives: (Tab 1) In the ALA-group, an improvement of dyspnea at 4-week follow-up was reported by 10/16 patients. The relief of dyspnea was experienced as substantial in 6/16, and as slight to moderate in 4/16. No change could be observed in 6/16.
V. Matzi et al. The initial symptom of hemoptysis subsided in 13/16 ALA-patients, radiological and/or clinical signs of poststenotic pneumonia subsided in 5/9 patients at 4-week follow-up. In the PhP-group, an improvement of dyspnea at 4-week follow-up was reported by 19/24 patients. The relief of dyspnea was experienced as substantial in 12/24, and as slight to moderate in 7/24; 5/24 patients felt no change. The initial symptom of hemoptysis subsided in 20/24 PhP patients. Radiological and/or clinical signs of poststenotic pneumonia subsided in 9/13 patients at 4-week follow-up. Improvement regarding dysphagia could be obtained and an at least semisolid diet was possible in all patients after PDT. At the 1-month follow-up, the mean reduction of dysphagia in the ALA-group was 1.4 levels, and 1.9 levels in the PhP-group. Statistical analysis showed a significant difference (P = 0.02; Mann—Whitney U-test) in favour of the PhPgroup.
Side effects and complications In neither group sunburn due to phototoxicity occurred. None of the patients in the PhP-group reported about a decrease in quality of life due to the long lasting necessity of skin protection. No major complications related to photosensitization, PDT or HBO occurred during or after the intervention. Minor complications like fever up to 39 ◦ C in the afternoon after PDT (26 in the ALAgroup and 44 in the PhP-group) as well as mild chest pain for 1 or 2 days (18 in the ALA-group and 34 in the PhP-group) were observed. All side effects could be managed conservatively and they did not require a hospitalization of more then 2 days postinterventionally.
Discussion The poor prognosis of patients with stenosis of the airways or the esophagus due to non-resectable neoplasms is a well known fact [7,16,17]. A rapid reopening of the stenosis at a low rate of complications and side-effects, resulting in a reduction of hospitalization and an increase in quality of life are the main goals in the treatment of these patients. Conventional laser therapy always results in thermal damage of the surrounding mucosa. Stenting is seldom practicable or useful beyond the level of the main or intermediate bronchi or in the region of the upper or lower esophageal sphincter. Due to the cumulative dosage to the mucosa, which
5-Aminolaevulinic acid compared to polyhematoporphyrin photosensitization must not surpass 20 Gy, the application of endoluminal brachyradiotherapy is also limited. Therefore, there is a need of alternative methods for the treatment of these patients. PDT has become a widely accepted method in the palliation of malignant bronchial and esophageal stenosis and is currently performed dependent on its availability [2—6]. PDT can be included into any local and/or systemic treatment protocol along with other modalities like Nd-YAG laser desobliteration, stenting, radiotherapy and chemotherapy. The guiding principle is that PDT is more selective than other treatment options and that it can be applied repetitively without a limitation of the cumulative dosage. However, due to the limited penetration of laser-light into the tumour tissue PDT cannot be expected to eliminate bulky tumour outside the lumen or in lymph nodes. Despite successful reports of tumour eradication in early stages of cancer [3—6], it is generally accepted that porphyrins are far from being ideal photosensitizers. The major drawback of PhP—PDT is a prolonged, clinically significant photosensitivity of the skin (8—12 weeks). Since the prognosis of patients with advanced lung or esophageal cancer is poor, the long lasting photosensitization of the skin may affect the quality of life. Therefore ALA, the period of skin photosensitivity of which is only 24 h, seems an attractive alternative [11,12,18]. There are few risks of serious systemic toxicity and it is administered orally. Furthermore, ALA, as reported [12,19], seems to offer a higher selectivity of tumour tissue than the conventional PhP photosensitizers Photofrin® or Photosan® . Whereas the ratio of tumour to benign tissue concentration is 3:1 for PhP [19] it is 6:1 for ALA because Pp IX is directly synthesized in tumour cells [12]. In contrast, porphyrin mainly localizes at the vascular stroma of the tumour tissue. However, the theoretically expected advantages of ALA—PDT in treatment of malignant esophageal and tracheo-bronchial stenosis advanced bronchogenic could not be confirmed in this study. Considering the main goals of palliative treatment of malignant bronchial and esophageal stenosis such as reduction of tumour stenosis and improvement of Karnofsky performance status as an indirect measurement of quality of life, PhP—PDT showed to be superior compared to ALA—PDT, though the depth of necrosis achieved by ALA in our study was superior to the one reported in the literature [20]. Only the lack of prolonged photosensitation of the skin could be noticed as an advantage: In our study, the patients in the ALA-group, who were kept in dimmed hospital rooms for 1 day, did not have problems regarding skin photosensitivity.
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Our results corroborate previous findings. Clinical studies of gastrointestinal tract tumours by Regula et al. [20] have shown that even when using ALA at 60 mg/kg body weight, it is not possible to produce necrosis more than 1 mm depth. This is in contrast to reports in the literature [12], where Pp IX fluorescence, used as an indirect method of measurement, showed intratumoural sensitizer concentrations to peak at 6—8 h after ALA administration. The concentrations seemed sufficient to enable a sequential destruction of more advanced tumours [19]. One explanation of these results may be that the maximum bolus dose of ALA which can be tolerated orally by patients is about 60 mg/kg body weight. Higher doses cause severe nausea with occasional vomiting and transient elevation of liver enzymes [20]. Regula et al. [20], achieved 8-mm depth of necrosis in transplanted tumours of hamster pancreas using an oral dose of ALA 400 mg/kg body weight. These results indicate that the ALA doses suggested in literature [20] and also used in the present study were too low for a substantial clinical effect. The availability of an intravenous preparation of ALA for clinical use might bring about a dramatic improvement, particularly since the dose required to achieve a given tissue level of Pp IX by intravenous application is likely to be about half the one required for oral medication [11—13]. The tumour necrosis of more than 1-mm depth, as achieved by ALA in the present study may be explained by the additional effect of hyperbaric oxygenation. However, the benefit of additional hyperbaric oxygenation in PDT has been demonstrated and discussed elsewhere [14,15]. Considering the potential disadvantage of prolonged photosensitization of the skin after PhP—PDT none of the patients in the PhP-group reported reduction of quality of life due to the long lasting necessity of sun protection. In conclusion, photosensitization with PhP compared to ALA seems to be more effective in PDT of malignant bronchial and esophageal stenosis. The oral application of a standardized dose of ALA (60 mg/kg body weight) is probably only at or just above the threshold level for producing any effect.
References [1] Barr H, Tralau CJ, Boulos PB, McRobert AJ, Tilly R, Bown SG. The contrasting mechanism of colonic collagen damage between photodynamic therapy and thermal injury. Photocm Photobiol 1987;46:795—800. [2] Moghissi K, Dixon K, Stringer M, Freeman T, Thorpe A, Brown S. The place of bronchoscopic photodynamic therapy in ad-
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V. Matzi et al. vanced unresectable lung cancer: experience of 100 cases. Eur J Card Thorac Surg 1999;15:1—5. Vincent R, Dougherty T. Photoradiation therapy in the treatment of advanced carcinoma of the trachea and bronchus. Proc Clin Biol Res 1984;170:759—66. Moghissi K, Parsons RJ, Dixon K. Photodynamic therapy for bronchial carcinoma with use of rigid bronchoscope. Lasers Med Sci 1991;7:381—5. McCaughan Jr JS, Ellison EC, Guy JT, et al. Photodynamic therapy for esophageal malignancy: a prospective twelveyear study. Ann Thorac Surg 1996;62:1005—10. Ell C. Clinical photodynamic therapy: where is it heading? Endoscopy 1998;30:408—11. Maier A, Tomaselli F, Gebhard F, Rehak P, Smolle J, SmolleJ¨ uttner FM. Palliation of advanced esophageal carcinoma by photodynamic therapy and irradiation. Ann Thorac Surg 2000;69:1006—9. Dougherty TJ, Cooper MT, Mang TS. Cutaneous phototoxic occurrences in patients receiving Photofrin. Lasers Med Surg 1990;10:485—8. Regula J, McRobert AJ, Gorhein A, et al. Photosensitisation and photodynamic therapy of esophaeal, duodenal and colorectal tumors using 5-animolaevulinic acid-induced protoporphyrin IX. Gut 1995;36:67—75. Moghissi K, Dixon K, Parsons RJ. A controlled trial of Nd:Yag laser vs. photodynamic therapy for advanced malignant bronchial obstruction. Lasers Med Sci 1993;8:269—73. Loh CS, McRobert AJ, Bedwell J, Regula J, Krasner N, Bown SG. Oral versus intraveneous administration of 5aminolaevulinic acid for photodynamic therapy. Br J Cancer 1993;68:41—51. Bedwell J, McRobert AJ, Phillips D, Bown SG. Fluorescence distribution and photodynamic effect of ALA-induced PPIX in the DMH rat colonic tumor model. Br J Cancer 1992:65. Maier A, Sullmann D, Anegg U, et al. In vivo determination of tumor optical parameters in esophageal carcinoma. Lasers Surg Med 2000;27:350—7. Maier A, Anegg U, Fell B, et al. Hyperbaric oxygen and photodynamic therapy in the treatment of advanced carcinoma of the cardia and the esophagus. Lasers Surg Med 2000;26:308—15. Tomaselli F, Maier A, Pinter H, Stranzel H, SmolleJuettner FM. Photodynamic therapy enhanced by hyperbaric oxygen in acute endoluminal palliation of malignant bronchial stenosis. Eur J Card Thorac Surg 2001;i19:549— 54. Wolf M, Havemann K. Prognostische Faktoren und Therapiestrategien beim kleinzelligen und nichtkleinzelligen Bronchialkarzinom. In: Drings P, Vogt-Moykopf I, editors. Thoraxtumoren. Berlin: Springer; 1998 (pp. 63— 81). Heier SK, Rothman KA, Heier LM, Rosenthal WS. Photodynamic therapy for obstructing esophageal cancer: light dosimetry and randomized comparison with Nd:YAG laser therapy. Gastroenterology 1995;109:63—72. Regula J, Ravi B, Bedwell J, McRobert AJ, Bown SG. Photodynamic therapy using 5-aminolaevulinic acid for experimental cancer—–evidence for prolonged survival. Br J Cancer 1994;70:248—54. Hinnen P, de Rooij FW, Terlouw EM, et al. Porphyrin biosynthesis in human Barrett’s esophagus and adenocar cinoma after ingestion of 5-aminolaevulinic acid. Br J Cancer 2000;83(4):539—4323. Regula J, McRobert AJ, Gorhein A, Buonaccorsi GA, Thorpe SM, Spencer GM. Photosensitisation and photodynamic therapy of esophaeal, duodenal and colorectal tumors us-
ing 5-animolaevulinic acid-induced protoporphyrin IX. Gut 1995;36:67—75.
Invited Comments By Mr Roger Ackroyd MB ChB, MD (Dist), FRCS (Eng), FRCS (Ed), FRCS (Gen Surg) Consultant Upper Gastrointestinal Surgeon Royal Hallamshire Hospital Glossop Road Sheffield S10 2JF UK Photodynamic therapy (PDT) has been shown to be effective in the treatment of many different types of malignancy, both in early and late disease, and many different photosensitisers have been used. One of the problems of PDT is the prolonged skin photosensitivity seen with some sensitisers, which can last for several months. However, as outlined in this paper, one of the newer agents, 5-aminolaevulinic acid (ALA), has several theoretical advantages over most of the others. As well as a reduced period of skin photosensitivity, ALA can be given orally and also produces increased tumour: normal selectivity and better mucosal selectivity. However, one of the major disadvantages of ALA-PDT is the reduced depth of penetration achieved, which may limit its clinical usefulness. Indeed, in this study its clinical effectiveness is less than that of PhP. This would fit in with the findings of other studies and results from our own unit are similar. We have found that ALA-PDT is safe and effective in the treatment of Barrett’s oesophagus [1,2], but that it has little effect on established oesophageal cancer [3]. On the other hand, the use of Photofrin® -PDT for Barrett’s oesophagus, although providing effective eradication of the columnar epithelium, does lead to a significant incidence of post-operative strictures [4,5]. However, Photofrin® -PDT provides effective ablation of advanced oesophageal cancers, where the risk of structuring is of little consequence, as these patients present with a stricture. Most photosensitisers will have certain advantages over others and there is no panacea sensitiser. Overall, this and other studies highlight the importance of choosing the correct sensitiser for the clinical situation in question. This brings about the attractive possibility of tailoring PDT treatment to best fit the relevant clinical scenario. Further research is now needed to determine the optimal clinical role for the various photosensitisers available.
References [1] Ackroyd R, Brown NJ, Davis MF, et al. Photodynamic therapy for dysplastic Barrett’s oesophagus: a prospec-
5-Aminolaevulinic acid compared to polyhematoporphyrin photosensitization tive double blind randomised placebo-controlled trial. Gut 2000;47:612—7. [2] Ackroyd R, Kelty CJ, Brown NJ, Stephenson TJ, Stoddard CJ, Reed MWR. Eradication of dysplastic Barrett’s oesophagus using photodynamic therapy: long-term follow-up. Endoscopy 2003;35:496—501. [3] Ackroyd R, Brown NJ, Davis MF, Stephenson TJ, Stoddard CJ, Reed MWR. Aminolaevulinic acid-induced photodynamic therapy in the treatment ofdysplastic Barrett’s oesophagus
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and adenocarcinoma. Lasers in Medical Science 1999;14:278— 85. [4] Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett’s oesophagus: follow-up in 100 patients. Gastrointestinal Endoscopy 1999;49:1—7. [5] Overholt BF, Panjehpour M, Halberg DL. Photodynamic therapy for Barrett’s oesophagus with dysplasia and/or early stage carcinoma: long-term results. Gastrointestinal Endoscopy 2003;58:183—8.
5-Aminolaevulinic acid compared to polyhematoporphyrin photosensitization for photodynamic therapy of malignant bronchial and esophageal stenosis: clinical experience Veronika Matzia, Alfred Maiera, Oliver Sankina, J¨ org Lindenmanna, uttner MDa,∗ Peter Rehakb, Freyja M. Smolle-J¨ a
Division of Thoracic and Hyperbaric Surgery, Department of Surgery, University of Medicine, Auenbruggerplatz 29, A-8036 Graz, Austria b Division of Biomedical Engineering and Computing, University of Medicine, Graz, Austria KEYWORDS 5-Aminolaevulinic acid; Polyhematoporphyrin and malignant bronchial and esophageal stenosis
∗
Summary Background and objective: Polyhematoporphyrins (PhP) as sensitizers for photodynamic therapy (PDT) in malignant bronchial and esophageal stenosis carry the risk of prolonged photosensitivity of the skin. New line sensitizers such as 5-aminolaevulinic acid (ALA) with low rates of skin phototoxicity appear to be promising alternatives. The aim of this study was to evaluate the efficacy of ALA compared to PhP for PDT regarding phototoxicity of the skin, reduction of tumour stenosis and tumour length and Karnofsky performance status. Patients and methods: After diagnostic work-up, photosensitization was done in 38 patients with ALA (60 mg/kg body weight, oral, 6—8 h prior to PDT) and in 51 patients with PhP (2 mg/kg body weight, i.v., 48 h before PDT). The light dose was calculated as 300 J/cm fibre tip. Light at 630 nm was applied using a pumped dye laser. In both groups, additional hyperbaric oxygenation was applied at a level of 2 bar absolute pressure. Results: Improvement regarding stenosis diameter, tumour length and Karnofsky performance status could be obtained in both treatment arms with a significant difference in favour of the PhP-group, P = 0.00073; 0.000014, and 0.00015, respectively. No sunburn or other major treatment related complications occurred in either treatment arms. Conclusion: Photosensitization with PhP compared to ALA seems to be more effective in PDT of malignant bronchial and esophageal stenosis. © 2004 Elsevier B.V. All rights reserved.
Corresponding author. Tel.: +43 316 385 3302; fax: +43 316 385 4679. E-mail address: [email protected] (F.M. Smolle-J¨ uttner)
1572-1000/$ — see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(04)00040-7
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Introduction Photodynamic therapy (PDT) has been shown to be a promising non-thermic laser technique, which produces localized tissue necrosis induced by light following administration of a photosensitizing drug. The drug is activated by illumination at a specific wavelength matching its absorption spectrum. Compared to thermic techniques, e.g. Nd:YAG-laser or radiotherapy, which usually affect all parts of the wall, damaging collagen fibres and smooth muscle, PDT is more selective, sparing the collagen fibres and hence enabling healing by regeneration [1]. However, the present status of PDT is far from being ideal. In addition to problems with oxygen supply during PDT and precise light dosimetry, there are still difficulties in finding the ideal sensitizer. Clinically, the most widely used sensitizers are hematoporphyrin derivatives. In spite of promising results in the treatment of malignant esophageal and tracheo-bronchial stenosis [2—9] the use of this type of sensitizer is associated with undesirable side effects, such as prolonged cutaneous photosensitivity persisting up to 3 months [10]. New sensitizers such as 5-aminolaevulinic acid (ALA), which combine acceptably low rates of skin phototoxicity and clinically useful tumour tissue specificity, appear to be promising alternatives [11,12]. 5-ALA is a naturally occurring precursor for the heme biosynthetic pathway, which is intracellularly converted into the active compound, protoporphyrine IX (Pp IX). Under normal conditions, the enzyme ALAsynthetase is regulated by a negative feedback control mechanism, which responds to changes in heme concentration. When exposed to a large amount of exogenous ALA, the biosynthetic pathway is overloaded, resulting in the accumulation of certain porphyrin intermediates, especially Pp IX [11]. In more recent studies [8—12], it was shown that tumour tissue can be destroyed by ALA-induced Pp IX photodynamic therapy. A drawback of ALA, however, is the fact that the depth of therapy-induced necrosis has been reported to be less than the one achieved by PhP [9,11]. The aim of this clinical study was to evaluate the use of 5-ALA compared to PhP in photodynamic therapy of malignant esophageal and tracheo-bronchial stenosis. Phototoxicity of the skin, reduction of tumour stenosis, and tumour length as well as an improvement of Karnofsky performance status were considered as main outcome variables. Improvement of dysphagia and dyspnea, as well as reduction of hemoptysis and poststenotic pneumonia were considered as second objectives. Since previous studies [14,15] have shown significant enhancement of the oxygen-dependent PDT-
V. Matzi et al. photoreaction by administration of hyperbaric oxygen (HBO), we used adjunctive HBO during PDT in all patients.
Patients and methods One hundred and one patients with malignant esophageal or tracheo-bronchial stenosis not eligible for resection treatment because of poor performance status, functional and/or anatomical inoperability, and/or refusal of surgery were randomized. Because of inconstant availability of either photosensitzer during the first half of the study period in Austria, 12 patients had to be secondarily excluded. Eighty-nine patients entered the study. The protocol was approved by the institutional ethical committee of the medical faculty at the University of Graz. Informed written consent was obtained from each patient. In 38 patients, photosensitization was done with ALA and in 51 patients, Photosan-3® (Seehof Laboratory, Wesselburenkoog, Germany; Fig. 1), a mixture of porphyrin oligomers, was administered. The patients were selected into two treatment arms independent of the stage of disease, histology, age, sex, tumour stenosis, tumour length and Karnofsky performance status (KPS). Diagnostic work-up and clinical staging were done by esophagoscopy, bronchoscopy, computed tomography scans of the chest, abdominal ultrasonography and bone scan. Functional inoperability was confirmed by electrocardiogram, spiroergometry, blood gas analysis and cardiac ultrasonography. In the ALA-group, the photosensitizer (5aminolaevulinic acid, Medac Research® Wedel, Germany) was orally administered at a dose of 60 mg/kg body weight, 6—8 h prior to PDT. Thirtyone patients were male and seven were female (mean age: 64 years). Squamous cell carcinoma was evident in 22 and adenocarcinoma in 16 cases. By clinical TNM staging, 12 patients were stage III and 26 in stage IV. The Karnofsky performance status was at a mean level of 78 (range: 60—90). In cases with tracheo-bronchial lesions the mean stenosis was 79% of the normal luminal diameter (range: 50—90%). All patients complained about dyspnea as well as hemoptysis. Nine patients showed additional radiological and clinical signs of poststenotic pneumonia. In patients with malignant esophageal lesions the mean stenosis diameter was 8.4 mm (range: 7—14 mm). The mean tumour length at the time of admission was 6.8 cm (range: 5—10 cm). At the time of admission, all patients complained about dysphagia of solid food (level 1), semisolid diet (level 2) and liquids (level 3) within the past
5-Aminolaevulinic acid compared to polyhematoporphyrin photosensitization 3 months. Nutrition was possible using semisolid and/or liquid food. Skin protection was done by a camouflage (Covermark® , Milan, Italy) for 24 h after photosensitization. In the PhP-group, the photosensitizer (Photosan3® , Seehof Laboratory, Wesselburenkoog, Germany) was administered intravenously at a dosage of 2 mg/kg body weight, 48 h prior to PDT. Thirtyseven patients were male and 14 were female (mean age: 66 years). Squamous cell carcinoma was evident in 28 and adenocarcinoma in 23 cases. By clinical TNM staging, 31 patients were stage III and 20 stage IV. The Karnofsky performance status was at a mean level of 70 (range: 60—80). In case of malignant tracheo-bronchial lesions the mean stenosis was 50% of the normal luminal diameter (range: 20—95%). All patients complained about dyspnea as well as hemoptysis. Thirteen patients showed additional radiological and clinical signs of poststenotic pneumonia. In patients with malignant esophageal lesions the mean stenosis diameter was 8.4 mm (range: 4—12 mm). The mean tumour length at the time of admission was 6.3 cm (range: 4—10 cm). All patients complaint about dysphagia level 1—3 and six patients complained of aphagia (level 4) and were not able to handle their saliva and parenteral nutrition before PDT became necessary. Skin protection was done by using a commercially available sun-blocker (Solgard; SP FARMA, Portugal) for 12 weeks. In case of severe tumour stenosis, PDT was carried out by using a fibre with a 2-cm tip radial light diffusing cylinder (Photo Dynamic Therapy® HgesmbH, 1190 Vienna, Austria), which was inserted through the biopsy channel of the endoscope. In case of moderate tumour stenosis, a 2 cm balloon applicator system (Photo Dynamic Therapy® HgesmbH) was used to perform a homogenous light distribution. During treatment, the radial light diffusing cylinder and/or balloon applicator system was positioned closely to the tumour surface. The light dose was calculated as 300 J/cm fibre tip [13]. Light at 630 nm was applied using a diode laser system [Ceramoptec® , Bonn, Germany]. Wavelength and light dose at the tip of the light diffuser were controlled before and after PDT. In both groups additional hyperbaric oxygenation, as reported earlier [14,15], at a level of 2 ATA in the walk-in hyperbaric chamber at the University Hospital of Graz (Waagner Biro® AG, Graz, Austria) was done. Oxygen was applied over a mechanical ventilator (Servo 900 C, Siemens, Erlangen, Germany). Before hyperbaric oxygenation, all patients had an ear, nose and throat check-up.
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Each treatment was performed under shortterm intravenous anaesthesia (Propofol 1% AstraZeneca® , Vienna, Austria) with endotracheal intubation. Monitoring included electrocardiogram, noninvasive continuous blood pressure control, tcp02 (TCM® , Radiometer Medical A/S, Copenhagen, Denmark).
Follow-up Follow-up investigations were scheduled at 1 and 4 weeks after combined PDT/HBO. The effects on tumour stenosis were assessed by endoscopy, chest X-ray, spirometry and subjective relief of dyspnea, hemoptysis and dysphagia as well as clinical signs of poststenotic pneumonia and laboratory parameters corresponding to inflammatory processes (WBC, CRP and fibrinogen). The Karnofsky performance status was recorded at each follow-up. The effect on tumour stenosis was estimated by comparing the pre- and postinterventional increase of luminal diameter measured at the point of maximum constriction. All luminal diameters were estimated by the easy passage of graduated Bronchoscopes of known diameter (3.2, 5, 6 and 7 mm) and/or easy passage of ballon catheters of known diameter (8—23 mm). The minimum lumen of the treated region was recorded at each endoscopy.
Additional treatment At least 4 weeks after combined PDT/HBO all patients were considered for further treatment, i.e. high-dose rate (HDR) brachyradiotherapy, external beam irradiation and/or chemotherapy, depending on the oncological situation and the patients consent. In the ALA-group, all patients received HDR brachyradiotherapy at a total dose of 15 Gy (5 Gy/per session). In 12 patients the treatment was completed by external beam irradiation (EBR) using the multiple field technique to administer a total dose of 40 Gy. Eight patients received three cycles of chemotherapy. In the PhP-group, all patients received HDR brachyradiotherapy (15 Gy). In 31 patients, radiotherapy was completed by EBR (40 Gy). Twenty-one patients received three cycles of chemotherapy.
Statistical analysis Statistical analysis was performed by Chi-square test, Fisher’s exact test and analysis of variance (ANOVA). Survival distribution was determined with the Kaplan—Meier survival table.
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Results Statistical analysis of qualitative variables showed no significant difference before entering the treatment schedule between both treatment arms as to sex (P = 0.71; Fisher’s exact test), localization (P = 0.80; Chi-square test), histology (P = 0.20; Chi-square test), and UICC-stage (P = 0.066; Kruskal—Wallis test). Karnofsky performance status (P = 0.0008; Kruskal—Wallis test) and stenosis diameter (P = 0.0001; Kruskal—Wallis test) showed a significant difference with a better KPS and a less degree of stenosis for the ALA-group before entering the treatment schedule However, for statistical analysis the difference from baseline to 4-week follow-up for each group was done.
Primary objectives: (Tab 1) In the ALA-group, the Karnofsky performance status showed little improvement. The mean value changed from baseline 78 to 4-week follow-up 79. In only five patients an improvement of 10% could be documented. The stenosis diameter in tracheobronchial lesions dropped from a mean value of 79% at baseline to 63%. In patients with esophageal lesions the mean decrease in diameter of stenosis was 2.8 mm at 4-week follow-up. The mean reduction of tumour length in esophageal lesions was 1.2 cm. In the PhP-group, the Karnofsky performance status improved by 10% in 26 patients and by 20% in 11 patients. In 14 patients no improvement was found. The mean value changed from 70 at baseline to 79 at 4-week follow-up. Statistical analysis showed a significant difference (P = 0.00015; ANOVA) in favour of the PhP-group. In tracheo-bronchial lesions the stenosis diameter dropped from a mean value of 50% at baseline to 19% and in patients with esophageal lesions the mean decrease of stenosis was 6.0 mm at 4-week follow-up. Statistical analysis showed a significant difference (P = 0.00073; ANOVA) in favour of the PhP-group. In esophageal stenosis the mean reduction of tumour length was 2.7 cm in the PhP-group, comparing favourably with the ALA-patients (P = 0.000014; Mann—Whitney U-test).
Secondary objectives: (Tab 1) In the ALA-group, an improvement of dyspnea at 4-week follow-up was reported by 10/16 patients. The relief of dyspnea was experienced as substantial in 6/16, and as slight to moderate in 4/16. No change could be observed in 6/16.
V. Matzi et al. The initial symptom of hemoptysis subsided in 13/16 ALA-patients, radiological and/or clinical signs of poststenotic pneumonia subsided in 5/9 patients at 4-week follow-up. In the PhP-group, an improvement of dyspnea at 4-week follow-up was reported by 19/24 patients. The relief of dyspnea was experienced as substantial in 12/24, and as slight to moderate in 7/24; 5/24 patients felt no change. The initial symptom of hemoptysis subsided in 20/24 PhP patients. Radiological and/or clinical signs of poststenotic pneumonia subsided in 9/13 patients at 4-week follow-up. Improvement regarding dysphagia could be obtained and an at least semisolid diet was possible in all patients after PDT. At the 1-month follow-up, the mean reduction of dysphagia in the ALA-group was 1.4 levels, and 1.9 levels in the PhP-group. Statistical analysis showed a significant difference (P = 0.02; Mann—Whitney U-test) in favour of the PhPgroup.
Side effects and complications In neither group sunburn due to phototoxicity occurred. None of the patients in the PhP-group reported about a decrease in quality of life due to the long lasting necessity of skin protection. No major complications related to photosensitization, PDT or HBO occurred during or after the intervention. Minor complications like fever up to 39 ◦ C in the afternoon after PDT (26 in the ALAgroup and 44 in the PhP-group) as well as mild chest pain for 1 or 2 days (18 in the ALA-group and 34 in the PhP-group) were observed. All side effects could be managed conservatively and they did not require a hospitalization of more then 2 days postinterventionally.
Discussion The poor prognosis of patients with stenosis of the airways or the esophagus due to non-resectable neoplasms is a well known fact [7,16,17]. A rapid reopening of the stenosis at a low rate of complications and side-effects, resulting in a reduction of hospitalization and an increase in quality of life are the main goals in the treatment of these patients. Conventional laser therapy always results in thermal damage of the surrounding mucosa. Stenting is seldom practicable or useful beyond the level of the main or intermediate bronchi or in the region of the upper or lower esophageal sphincter. Due to the cumulative dosage to the mucosa, which
5-Aminolaevulinic acid compared to polyhematoporphyrin photosensitization must not surpass 20 Gy, the application of endoluminal brachyradiotherapy is also limited. Therefore, there is a need of alternative methods for the treatment of these patients. PDT has become a widely accepted method in the palliation of malignant bronchial and esophageal stenosis and is currently performed dependent on its availability [2—6]. PDT can be included into any local and/or systemic treatment protocol along with other modalities like Nd-YAG laser desobliteration, stenting, radiotherapy and chemotherapy. The guiding principle is that PDT is more selective than other treatment options and that it can be applied repetitively without a limitation of the cumulative dosage. However, due to the limited penetration of laser-light into the tumour tissue PDT cannot be expected to eliminate bulky tumour outside the lumen or in lymph nodes. Despite successful reports of tumour eradication in early stages of cancer [3—6], it is generally accepted that porphyrins are far from being ideal photosensitizers. The major drawback of PhP—PDT is a prolonged, clinically significant photosensitivity of the skin (8—12 weeks). Since the prognosis of patients with advanced lung or esophageal cancer is poor, the long lasting photosensitization of the skin may affect the quality of life. Therefore ALA, the period of skin photosensitivity of which is only 24 h, seems an attractive alternative [11,12,18]. There are few risks of serious systemic toxicity and it is administered orally. Furthermore, ALA, as reported [12,19], seems to offer a higher selectivity of tumour tissue than the conventional PhP photosensitizers Photofrin® or Photosan® . Whereas the ratio of tumour to benign tissue concentration is 3:1 for PhP [19] it is 6:1 for ALA because Pp IX is directly synthesized in tumour cells [12]. In contrast, porphyrin mainly localizes at the vascular stroma of the tumour tissue. However, the theoretically expected advantages of ALA—PDT in treatment of malignant esophageal and tracheo-bronchial stenosis advanced bronchogenic could not be confirmed in this study. Considering the main goals of palliative treatment of malignant bronchial and esophageal stenosis such as reduction of tumour stenosis and improvement of Karnofsky performance status as an indirect measurement of quality of life, PhP—PDT showed to be superior compared to ALA—PDT, though the depth of necrosis achieved by ALA in our study was superior to the one reported in the literature [20]. Only the lack of prolonged photosensitation of the skin could be noticed as an advantage: In our study, the patients in the ALA-group, who were kept in dimmed hospital rooms for 1 day, did not have problems regarding skin photosensitivity.
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Our results corroborate previous findings. Clinical studies of gastrointestinal tract tumours by Regula et al. [20] have shown that even when using ALA at 60 mg/kg body weight, it is not possible to produce necrosis more than 1 mm depth. This is in contrast to reports in the literature [12], where Pp IX fluorescence, used as an indirect method of measurement, showed intratumoural sensitizer concentrations to peak at 6—8 h after ALA administration. The concentrations seemed sufficient to enable a sequential destruction of more advanced tumours [19]. One explanation of these results may be that the maximum bolus dose of ALA which can be tolerated orally by patients is about 60 mg/kg body weight. Higher doses cause severe nausea with occasional vomiting and transient elevation of liver enzymes [20]. Regula et al. [20], achieved 8-mm depth of necrosis in transplanted tumours of hamster pancreas using an oral dose of ALA 400 mg/kg body weight. These results indicate that the ALA doses suggested in literature [20] and also used in the present study were too low for a substantial clinical effect. The availability of an intravenous preparation of ALA for clinical use might bring about a dramatic improvement, particularly since the dose required to achieve a given tissue level of Pp IX by intravenous application is likely to be about half the one required for oral medication [11—13]. The tumour necrosis of more than 1-mm depth, as achieved by ALA in the present study may be explained by the additional effect of hyperbaric oxygenation. However, the benefit of additional hyperbaric oxygenation in PDT has been demonstrated and discussed elsewhere [14,15]. Considering the potential disadvantage of prolonged photosensitization of the skin after PhP—PDT none of the patients in the PhP-group reported reduction of quality of life due to the long lasting necessity of sun protection. In conclusion, photosensitization with PhP compared to ALA seems to be more effective in PDT of malignant bronchial and esophageal stenosis. The oral application of a standardized dose of ALA (60 mg/kg body weight) is probably only at or just above the threshold level for producing any effect.
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Invited Comments By Mr Roger Ackroyd MB ChB, MD (Dist), FRCS (Eng), FRCS (Ed), FRCS (Gen Surg) Consultant Upper Gastrointestinal Surgeon Royal Hallamshire Hospital Glossop Road Sheffield S10 2JF UK Photodynamic therapy (PDT) has been shown to be effective in the treatment of many different types of malignancy, both in early and late disease, and many different photosensitisers have been used. One of the problems of PDT is the prolonged skin photosensitivity seen with some sensitisers, which can last for several months. However, as outlined in this paper, one of the newer agents, 5-aminolaevulinic acid (ALA), has several theoretical advantages over most of the others. As well as a reduced period of skin photosensitivity, ALA can be given orally and also produces increased tumour: normal selectivity and better mucosal selectivity. However, one of the major disadvantages of ALA-PDT is the reduced depth of penetration achieved, which may limit its clinical usefulness. Indeed, in this study its clinical effectiveness is less than that of PhP. This would fit in with the findings of other studies and results from our own unit are similar. We have found that ALA-PDT is safe and effective in the treatment of Barrett’s oesophagus [1,2], but that it has little effect on established oesophageal cancer [3]. On the other hand, the use of Photofrin® -PDT for Barrett’s oesophagus, although providing effective eradication of the columnar epithelium, does lead to a significant incidence of post-operative strictures [4,5]. However, Photofrin® -PDT provides effective ablation of advanced oesophageal cancers, where the risk of structuring is of little consequence, as these patients present with a stricture. Most photosensitisers will have certain advantages over others and there is no panacea sensitiser. Overall, this and other studies highlight the importance of choosing the correct sensitiser for the clinical situation in question. This brings about the attractive possibility of tailoring PDT treatment to best fit the relevant clinical scenario. Further research is now needed to determine the optimal clinical role for the various photosensitisers available.
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5-Aminolaevulinic acid compared to polyhematoporphyrin photosensitization tive double blind randomised placebo-controlled trial. Gut 2000;47:612—7. [2] Ackroyd R, Kelty CJ, Brown NJ, Stephenson TJ, Stoddard CJ, Reed MWR. Eradication of dysplastic Barrett’s oesophagus using photodynamic therapy: long-term follow-up. Endoscopy 2003;35:496—501. [3] Ackroyd R, Brown NJ, Davis MF, Stephenson TJ, Stoddard CJ, Reed MWR. Aminolaevulinic acid-induced photodynamic therapy in the treatment ofdysplastic Barrett’s oesophagus
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and adenocarcinoma. Lasers in Medical Science 1999;14:278— 85. [4] Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett’s oesophagus: follow-up in 100 patients. Gastrointestinal Endoscopy 1999;49:1—7. [5] Overholt BF, Panjehpour M, Halberg DL. Photodynamic therapy for Barrett’s oesophagus with dysplasia and/or early stage carcinoma: long-term results. Gastrointestinal Endoscopy 2003;58:183—8.
