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Ann Thorac Surg 2001;72:1136-1140
© 2001 The Society of Thoracic Surgeons
a Department of Surgery, Division of Thoracic and Hyperbaric Surgery, University of Graz Medical School, Graz, Austria
b Department of Surgery, Division of Biomedical Engineering and Computing, University of Graz Medical School, Graz, Austria
Accepted for publication June 18, 2001.
Address reprint requests to Dr Maier, Department of Surgery, Division of Thoracic and Hyperbaric Surgery, University of Graz Medical School, Auenbruggerplatz 29 A-8036, Graz, Austria
e-mail: alfred.maier{at}klinikum-graz.at
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Abstract |
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 Top Abstract IntroductionPatients and methodsResultsCommentReferences |
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Methods. After diagnostic workup, photosensitization was done in 22 patients with ALA (60 mg/kg body weight, oral, 6 to 8 hours before PDT) and in 27 patients with a hematoporphyrin derivative (2 mg/kg body weight, intravenously, 48 hours before PDT). The light dose was calculated as 300 J/cm fiber 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 absolute atmospheric pressure.
Results. Improvement regarding dysphagia, stenosis diameter, and tumor length could be obtained in both treatment arms with a significant difference in favor of the HpD group (p = 0.02; p = 0.0000; and p = 0.000014, respectively). A questionnaire of patients in the HpD group confirmed that the ability of swallowing a meal was superior compared with the discomfort from limitation to sun exposure. No sunburn or other major treatment-related complication occurred in both treatment arms.
Conclusions. Despite the limitations of a nonrandomized study, photosensitzation with HpD seems to be more effective in PDT of advanced esophageal carcinoma compared with ALA.
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsCommentReferences |
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Clinically, the most widely used sensitizers are hematoporphyrin derivatives (HpD). Despite promising results in the treatment of advanced esophageal cancer [2–4] the use of this type of sensitizer is associated with undesirable side effects, such as prolonged cutaneous photosensitivity persisting up to 3 months [5]. New sensitizers, such as 5-aminolaevulinic acid (ALA), which combine acceptably low rates of skin phototoxicity and clinically useful tumor tissue specificity, appear to be promising alternatives [6–8]. The 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 ALA synthetase is regulated by a negative feedback control mechanism that 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 [9]. In more recent studies [10–13], it was shown that tumor tissue can be destroyed by ALA-induced Pp IX photodynamic therapy.
The aim of this clinical pilot study was to evaluate the use of ALA compared to HpD in photodynamic therapy of advanced esophageal cancer. Phototoxicity of the skin, reduction of dysphagia, tumor stenosis and length, as well as an improvement of Karnovsky performance status were considered as main outcome variables.
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsCommentReferences |
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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 22 patients, photosensitization was done with ALA and in 27 patients, an HpD was administered. The patients were selected into two treatment arms independent of the stage of disease, histology, age, sex, dysphagia score, tumor stenosis, tumor length, and Karnovsky performance status. The most important selecting factor for the distribution between the two treatment arms was the availability of the selected photosensitzer. In the first 11 months of the study only HpD was available for PDT in Austria; however, from December 1999 on, both sensitizers were used depending on the expected compliance of the patient for sun protection.
Diagnostic workup and clinical staging were done by barium esophagogram, esophagogastroscopy, bronchoscopy, computed tomographic scans of the chest and the abdomen, abdominal ultrasonography, and bone scan. Unfortunately, endoscopic ultrasound being the most reliable method for staging and postinterventional follow-up was not available during the study period. Functional inoperability was confirmed by electrocardiogram, sprioergometry, blood gas analysis, and cardiac ultrasonography. 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 3 months. Nutrition was possible using semisolid or liquid food. Six patients in the HpD group complained of aphagia (level 4) and were not able to handle their saliva and parenteral nutrition before PDT became necessary. Weight loss of at least 5 kg within the past 2 months as well as insufficient nutrition was evident in most patients.
In the ALA group (Table 1), the photosensitizer (5-aminolaevulinic acid; Medac Research, Wedel, Germany) was administered orally at a dose of 60 mg/kg body weight, 6 to 8 hours before PDT. None of the patients reported vomiting after the oral administration of ALA. Eighteen patients were men and 4 were women (mean age, 69 years). Squamous cell carcinoma was evident in 10 and adenocarcinoma in 12 patients. Using TNM clinical staging, 4 patients were in stage III and 18 in stage IV. The Karnovsky performance status was 80 in 15 patients and 90 in 7 (mean, 83). The dysphagia score before therapy was level 1 in 3 patients, level 2 in 4, and level 3 in 15 patients. The mean stenosis diameter was 8.4 mm (range, 7 to 14 mm). The mean tumor length at the time of admission was 6.8 cm (range, 5 to 10 cm). Skin protection was done by a camouflage (Covermark, Milan, Italy) for 24 hours after photosensitization.
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The PDT was carried out by using a fiber with a 2-cm tip radial light diffusing cylinder (Photo Dynamic Therapy HgesmbH, Vienna, Austria), which was inserted through the biopsy channel of the endoscope. During treatment, the light diffuser was closely applied to the tumor surface, although this was limited throughout the treatment because of esophageal wall motion, heart beat, respiration, and sometimes coughing. The light dose was calculated as 300 J/cm of fiber. Light at 630 nm was applied by a neodymium:yttrium-aluminum garnet laser having a dye module (Laserscope Surgical Systems, Gwent, UK). 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], at a level of 2 absolute atmospheric pressure in the walk-in hyperbaric chamber at the University Hospital of Graz (Waagner Biro AG, Graz, Austria) was done. Oxygen was applied using a Scuba valve systeme (Oxidem 2000, Dräger, Lübeck, Germany). Before hyperbaric oxygenation, all patients had an ear, nose, and throat check-up.
Each treatment was performed under short-term intravenous anesthesia (propofol 1%; AstraZeneca, Vienna, Austria) with endotracheal intubation and spontaneous breathing. Monitoring included electrocardiogram, noninvasive continuous blood pressure control, transcutaneous p02 (tcp02) (TCM, Radiometer Medical A/S, Copenhagen, Denmark).
Two to 3 days after PDT, endoscopy was repeated and necrotic tissue was removed mechanically when necessary. The depth of tumor necrosis was determined by the postdebridement increase in luminal diameter measured at the maximal point of constriction. All luminal diameters were confirmed by noting the easy passage of graduated bronchoscopes (3.2, 5, 6, and 7 mm) and esophagogastroscopes (9, 11.6, and 14 mm) with known diameters, the easy passage of Savary-Gillard dilators of known diameters, or both. The patients then underwent repetitive endoscopy, first after 1 month and then once every 3 months. Stage of disease, Karnovsky performance status, dysphagia score, diet, and complications were recorded at each follow-up visit. Biopsy samples, tumor length, and minimal opening diameter were recorded at each endoscopy. Computed tomography scans of the chest and abdomen were performed every 6 months. An increase in tumor length and dysphagia at follow-up was the indication for repeat PDT treatment. No treatment was repeated within 3 months after the first PDT session.
Statistical analysis
Statistical analysis was performed by 
2 test, Fisher’s exact test and Mann-Whitney U test. Survival distribution was determined with the Kaplan-Meier survival table.
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Results |
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TopAbstractIntroductionPatients and methodsResultsCommentReferences |
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Improvement regarding dysphagia could be obtained and a semisolid diet was at least possible in all patients after PDT (Table 2). At the 1-month follow-up, the mean reduction of dysphagia in the ALA group was 1.4 (95% confidence interval 1.0 to 1.7) and in the HpD group, 1.9 (95% confidence interval 1.6 to 2.1). Statistical analysis showed a significant difference (p = 0.02; Mann-Whitney U test) in favor of the HpD group. After 1 month, the stenosis decreased in both treatment arms and showed a significant difference in favor of the HpD group (p = 0.0000; Mann-Whitney U test). In the ALA group, the mean decrease in stenosis was 2.8 mm (95% confidence interval 2.1 to 3.5) and in the HpD group 6.0 mm (95% confidence interval 5.3 to 6.7). The tumor length also decreased in both treatment arms and showed a significant difference in favor of the HpD group (p = 0.000014; Mann-Whitney U test). In the ALA group, the mean reduction of tumor length was 1.2 cm (95% confidence interval 0.7 to 1.7) and in the HpD group 2.7 cm (95% confidence interval 2.4 to 3.0).
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No barotrauma of the ear due to hyperbaric oxygenation could be observed. Considering the different types of photosensitization treatments of the skin no sunburn occurred within both treatment arms. A questionnaire of patients in the HpD group confirmed that the ability of swallowing a meal was superior compared to the discomfort from limitation to sun exposure. Hospitalization in both treatment arms was 4 to 6 days.
Minor complications such as postinterventional odynophagia (13 in the HpD group and 9 in the ALA group), fever up to 39.0°C in the afternoon of the interventional day (8 in the HpD group and 5 in the ALA group), and chest pain for 1 or 2 days (13 in the HpD group and 9 in the ALA group) could be observed. After oral administration of ALA (60 mg/kg body weight), dissolved in 250 mL of orange juice, all patients complained about nausea. However, with the additional use of antiemetic drugs (Ondansetron; Zofran, GlaxoWellcome Pharma GmbH, Vienna, Austria) the symptoms disappeared.
No major treatment-related complication occurred within both treatment arms. The 30-day mortality rate was 0%.
Survival
The median survival time for the ALA group was 8.0 months, compared with 9.0 months for the HpD group (Fig 1). There was no significant difference between both treatment arms (p = 0.44; log-rank test).
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Comment |
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TopAbstractIntroductionPatients and methodsResultsCommentReferences |
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Despite successful reports of tumor eradication [2, 4, 14], it is generally accepted that HpD are far from being the ideal photosensitizer. The major drawback of HpD–PDT is prolonged clinically significant photosensitivity of the skin (8 to 12 weeks). Because the prognosis of patients with advanced esophageal carcinoma is poor, with survival rates of 6 to 12 months [4, 14], the prolonged photosensitization of the skin may affect the quality of life. Therefore, ALA is an attractive prospective photosensitizing agent because skin photosensitivity is limited to 24 hours [7]; there are few risks of serious toxicity and it can be given orally. Accordingly, the patients in the ALA group of this study, who were kept in dimmed hospital rooms for 1 day, did not have problems regarding skin photosensitivity after 24 hours.
Despite rapid reabsorbtion of ALA as reported [8], the oral application of a photosensitizing drug always carries the risk of reabsorbtion disturbance resulting in an inadequate tissue concentration at the tumor site. However, in this study none of the patients reported vomiting after the oral administration of ALA. Therefore, no confirmations of the concentration of the photosensitizer at the tumor site were done. As reported in literature [8], when Pp IX fluorescence is used as an indirect method of measurement, intratumoral sensitizer concentrations peak 6 to 8 hours after ALA administration, sufficient to enable a sequential destruction of more advanced tumors [10]. Furthermore, ALA, as reported [8, 16], seems to offer a higher selectivity of tumor tissue than the conventional photosensitizer HpD. Whereas the ratio of tumor to benign tissue concentration is 3:1 for HpD [17] it is 6:1 for ALA because Pp IX is directly synthesized in tumor cells [8]. In contrast, HpD mainly localizes at the vascular stroma of the tumor tissue.
However, the theoretically expected advantages of ALA PDT in treatment of advanced esophageal carcinoma could not be confirmed in this pilot study. Considering the main goals of palliative treatment of esophageal carcinoma such as improvement of dysphagia and reduction of tumor stenosis, HpD–PDT showed significant improvement compared to ALA PDT. One explanation for these results may be that the maximum bolus dose of ALA that 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 [6]. Clinical studies of gastrointestinal tract tumors by Regula and colleagues [6] 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. In contrast, Regula and associates [18] achieved 8 mm depth of necrosis in transplanted tumors of hamster pancreas using an oral dose of 400 mg/kg body weight ALA. These results indicate that the drug doses suggested in literature [6, 7, 10, 13, 19] and also used in this study were too low. This may be improved when an intravenous preparation of ALA is available for clinical use, particularly as the dose required intravenously is likely to be about half that needed orally to achieve the same tissue levels of Pp IX [7]. The achieved depth of tumor necrosis of 2.1 to 3.5 mm (mean, 2.8 mm) as reported in this study may be explained by the additional effect of hyperbaric oxygenation. However, the benefit of additional hyperbaric oxygenation in PDT has been demonstrated in the literature [14, 20, 21]. Experimental studies [22–24] and clinical studies [14] have shown that the presence of molecular oxygen in tumor tissue is crucial for the effectiveness of PDT. The use of hyperbaric oxygen to increase the availability of oxygen in hypoxic tissue is well known. Jirsa [20] and Dong [21] and their colleagues documented the enhanced effect of PDT combined with hyperbaric oxygenation (HBO) in mice. In further clinical studies [25, 26] the benefit of additional HBO could be well documented. However, the availibility of HBO in addition to PDT is limited and therefore, it could not be recommended as a standard. Nevertheless, application of normobaric 100% oxygen during PDT should be done to guarantee optimal oxygenation at the tumor site.
In conclusion, despite the clear limitations of a nonrandomized study, photosensitization with HpD compared to ALA seems to be more effective in PDT with advanced carcinoma of the esophagus. 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. To increase the Pp IX levels, ALA could be given intravenously. Nevertheless, photodynamic therapy of advanced esophageal carcinoma has shown to be an important treatment option to handle patients complaining of dysphagia. The major advantage of PDT in this concept is that there is no limitation to repeat the treatment. Therefore, PDT should be used in a multimodality concept as reported earlier [4].
However, to confirm the results of this pilot study as well as the effect of additional HBO, a randomized, observer-blinded, trial has been initiated. Recommendations concerning the use of the photosensitizer with or without HBO in the treatment of advanced esophageal cancer will be made after finishing the ongoing study.
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