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Ann Thorac Surg 2000;69:1006-1009
© 2000 The Society of Thoracic Surgeons

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ORIGINAL ARTICLES: GENERAL THORACIC

Palliation of advanced esophageal carcinoma by photodynamic therapy and irradiation

^a Division of Thoracic and Hyperbaric Surgery, Department of Surgery, Karl-Franzens University Medical School, Graz, Austria
^b Department of Radiotherapy, Karl-Franzens University Medical School, Graz, Austria
^c Division of Biomedical Engineering and Computing, Karl-Franzens University Medical School, Graz, Austria
^d Department of Dermatology, Karl-Franzens University Medical School, Graz, Austria

Address reprint requests to Dr Maier, Department of Surgery, Division of Thoracic and Hyperbaric Surgery, Karl-Franzens University of Graz, Auenbruggerplatz 29, A-8036 Graz, Austria

	Abstract

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Background. We wanted to determine the role of photodynamic therapy in a multimodal approach for the treatment of patients with advanced cancer of the esophagus.

Methods. We reviewed the cases of 119 patients with nonresectable esophageal carcinoma who underwent endoluminal palliation. Twenty-one patients required initial dilation and tumor obliteration with a neodymium:yttrium-aluminum-garnet laser prior to therapy. Forty-four patients received photodynamic therapy followed by brachyradiotherapy, and 75 patients were treated with brachyradiotherapy. In both groups, some patients also received external-beam irradiation.

Results. Photodynamic therapy produced a significant difference in relieving stenosis caused by tumor stenosis (mean, 6.6 mm; p = 0.0000). The dysphagia score improved by one to three levels in all patients, with a significant difference in favor of PDT (p = 0.0003). The mean number of overall treatment sessions was four (range, one to seven). The rate of major complications was 9.2%. Four esophageal perforations occurred, three after intervention and one spontaneously 5 months later. Four esophagorespiratory tract fistulas developed several months after combined PDT and irradiation. The mean overall survival was 7.7 months, and analysis of variance revealed a significant difference in favor of PDT and external-beam irradiation (p = 0.0129 and p = 0.0001, respectively).

Conclusions. Photodynamic therapy has been shown to be an effective palliative treatment of advanced esophageal cancer. However, proper patient selection is necessary to prevent serious complications.

	Introduction

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Advanced esophageal carcinoma is associated mainly with dysphagia. The inability to swallow a regular diet is one of the most severe symptoms reducing the quality of life for patients with an incurable disease and short life expectancy [1, 2]. Therefore, the main goal in the palliation of patients with advanced esophageal carcinoma is a decrease in dysphagia to improve the quality of life. A variety of tumoricidal palliative measures allow at least a limited oral diet, but they require hospitalization. Many published reports discuss different combinations of tumoricidal procedures such as brachytherapy [3], external-beam irradiation [4], tumor obliteration with a laser [5] or cautery, stenting, [6], chemotherapy [7], and photodynamic therapy (PDT) [8–10]. Irradiation, tumor obliteration, and intubation are well-known, accepted strategies in the palliation of advanced esophageal carcinoma. However, on the basis of the pioneer work by Dougherty and colleagues [11] with PDT, increasing attempts have been made to use dye lasers to esophageal carcinoma. Early results of PDT in esophageal cancer are promising and may help to lessen dysphagia, the symptom with the greatest impact on the quality of life of patients with an incurable disease.

The aim of this nonrandomized comparative study was to determine the effect of PDT in a multimodal approach for the palliation of advanced esophageal carcinoma.

	Material and methods

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From January 1993 to December 1997, we treated 119 patients with advanced esophageal carcinoma who were not eligible for resection because of tumor involvement of the adjacent tissue, poor performance status plus inoperable status as a result of comorbidity, refusal of surgical intervention, or a combination of these reasons. Because of dysphagia, endoluminal palliation was considered the treatment of choice.

Ninety-six patients (80.7%) were men (mean age, 67 years; range, 42 to 93 years), and 23 patients (19.3%) were women (mean age, 65 years; range, 27 to 83 years). Squamous cell carcinoma was present in 68 patients (57.1%) and adenocarcinoma in 51 (42.9%). Using the TNM system of clinical staging [12], 80 patients were in stage III and 39, in stage IV: T3 = 46 patients (38.7%) and T4 = 73 (61.3%); N1 = 65 (54.6%) and NX = 54 (45.4%); and M0 = 80 (67.2%) and M1 = 39 (32.8%). The site of the tumor was in the distal third of the esophagus in 79 patients (66.4%), the middle third in 30 (25.2%), and the proximal third in 10 (8.4%).

Diagnostic workup and clinical staging were done with barium esophagography, esophagogastroscopy, bronchoscopy, computed tomographic scans of the chest and abdomen, abdominal ultrasonography, and bone scan. Endoscopic ultrasound was not available during the study period. Inoperability because of comorbidity was confirmed by electrocardiography, spiroergometry, blood gas analysis, and cardiac ultrasonography. At the time of admission, most patients complained of dysphagia on a semisolid diet (level 2) (53 patients) or liquids (level 3) (45 patients). Twenty-one patients complained of aphagia (level 4) and were not able to handle saliva. Weight loss of more than 5 kg in the last 3 months was evident in all patients. The mean tumor-related stenosis at the time of admission was 7.7 mm in diameter (range, 4 to 11 mm).

Treatment
Twenty-one patients required initial dilation and tumor obliteration with a neodymium:yttium-aluminum-garnet (Nd:YAG) laser prior to therapy because extensive tumor stenosis allowed the passage of only a 3.2- or 5-mm bronchoscope. A flexible guidewire was passed through the endoscope, and careful dilation to at least 9 mm was done. A 7-mm bronchoscope was then passed over the guidewire, and retrograde Nd:YAG laser obliteration was performed. The occurrence of perforation was excluded by esophagography using a water-soluble contrast medium.

Forty-four patients received PDT followed by brachyradiotherapy. Seventy-five patients refused PDT and were treated with high-dose rate (HDR) brachyradiotherapy. In both groups some patients also received external-beam irradiation (25 patients in the PDT and brachytherapy group and 17 patients in the brachytherapy group).

After giving informed written consent, the patients in the PDT group received 2 mg/kg of hematoporphyrine polyester (Seehof Laboratory, Wesselburenkoog, Germany), administered intravenously. Forty-eight hours after photosensitization, PDT was done using a fiber with a 2-cm radial light-diffusing cylinder (Photo Dynamic Therapy, HGesmbH, Vienna, Austria), which was inserted through the biopsy channel of the endoscope. The diffuser was applied close to the tumor surface, although such placement was limited throughout treatment because of esophageal wall motion, respiration, heart beat, and sometimes cough. The light dose was calculated as 300 j/cm of fiber. Light intensity of 630 nm was applied by a KTP-Nd:YAG laser with DYE-box (Laserscope; Surgical Systems, Gwent, UK). Wavelength and light dose at the tip of the light diffuser were controlled before and after PDT.

Two to three days after PDT, endoscopy was repeated and necrotic tissue was removed mechanically. Endoscopy was performed again after 1 month and then periodically every 3 months. In the case of local tumor progression, repeat treatment of the residual tumor was done after another injection of hematoporphyrin-derivative after several months. Photodynamic therapy was not repeated within 3 months. Sixty-five injections of hematoporphyrin derivative were administered to 44 patients (mean number per patient, 1.5). Stage of disease, Karnofsky performance status, diet, and complications were recorded at each follow-up visit. Biopsy samples and minimal opening diameter were recorded at each endoscopy. The diameter of stenosis was estimated by the easy passage of endoscopes (3.2 mm, 5.0, 6.0, 7.0, 9, and 12 mm) and Savary-Gillard dilators of known diameter.

Iridium192 brachyradiotherapy was given to all patients. Insertion of the afterloading catheter (outer diameter, 6 mm and 8 mm, Selectron and Microselectron devices, respectively [Nucletron Inc, Veenendaal, The Netherlands]; source activity, 2 to 10 Ci) was done endoscopically in all patients without any problems. We administered 5 Gy per session calculated at a distance of 1 cm from the surface of the source. The total number of sessions ranged between one and four (5 Gy, 4 patients; 10 Gy, 13 patients; 15 Gy, 100 patients; 20 Gy, 2 patients; mean dose, 14.2 Gy), depending on the endoscopic findings and the level of dysphagia. The interval between sessions was 3 to 7 days. In 42 patients (25 in the PDT and brachytherapy group and 17 in the brachytherapy group) in fair general condition (Karnofsky performance status > 80), the treatment was completed by external-beam irradiation using the multiple-field technique to administer a total dose of between 30 and 60 Gy (mean dose, 44 Gy).

Photodynamic therapy brachyradiotherapy, tumor obliteration, and dilation were done with the patient under short-term intravenous anesthesia (propofol 1%; Zeneca, Vienna, Austria) combined with topical anesthesia (Xylocaine 1% (Gebro Broschek GmbH) [lidocaine hydrochloride], Fieberbrunn, Austria) and breathing spontaneously supported by nasal oxygen administration (4 to 6 L/min). Monitoring was done using electrocardiography, noninvasive continuous blood pressure control, and pulse oximetry.

Statistical analysis
Statistical analyses were performed by two-way analysis of variance with the factors PDT and external-beam irradiation (no multiple-group comparisons were done) and by the ² test. Survival analysis was determined by assumption of log-normal distribution analysis of variance and of log-transformed data.

	Results

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In terms of the various treatment regimen, no differences regarding sex (p = 0.75), T (p = 0.36) and N (p = 0.21) stages, histology (p = 0.12), site of tumor (p = 0.66), and dysphagia score prior to treatment (p = 0.25) were detected. The Karnofsky performance status prior to therapy was significantly higher in patients treated with the multinodal concept than in patients given only the basic treatment of HDR brachyradiotherapy (p = 0.00001). Similarly, patients with M0 disease had a better performance status than those in stage M1, who were more often treated only by HDR brachyradiotherapy (p = 0.0069).

At the 3-month follow-up, the Karnofsky performance status increased by 10 to 20 units in 117 patients. In only 2 patients (1 given HDR brachyradiotherapy and 1, PDT) did the status decrease. However, there was no significant difference (p = 0.28) regarding the applied treatment regimen. The dysphagia score improved in all patients by one to three levels, with a significant difference in favor of PDT (p = 0.0003). The mean opening diameter of tumor-related stenosis increased from 7.7 mm prior to therapy to 12.8 mm 3 months after treatment. The mean increase after HDR brachyradiotherapy alone was 4.1 mm; after HDR brachyradiotherapy and external-beam irradiation, 4.5 mm; after PDT followed by HDR brachyradiotherapy, 6.6 mm; and after the multimodal approach with PDT, HDR brachyradiotherapy, and external-beam irradiation, 6.4 mm. In terms of the decrease in stenosis, analysis of variance revealed PDT to be highly significant (p = 0.0000).

The number of overall treatment sessions (mean number, four; range 1–7) depended on the degrees of tumor-related stenosis and the need of laser obliteration and dilation prior to therapy. In most patients, three sessions of HDR brachyradiotherapy were done. In patients receiving PDT, one or two additional treatment sessions were necessary.

Survival
The mean overall survival was 7.7 months. The mean survival by treatment was as follows: brachyradiotherapy, 5.6 months; brachyradiotherapy and external-beam irradiation, 7.7 months; and PDT brachyradiotherapy, 6.3 months; and combined PDT, HDR brachyradiotherapy, and external-beam irradiation, 13.0 months (Fig 1). Analysis of variance showed a significant difference in favor of PDT and external-beam irradiation (p = 0.0129 and p = 0.0001, respectively). This finding, however, is biased by the fact that the groups without external-beam irradiation contained patients who died before entering the irradiation regimen.

View larger version (18K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival distribution by treatment group to palliate advanced esophageal carcinoma. (EBT = external-beam irradiation; Ir = iridium 192; PDT = photodynamic therapy.)

Severe hemorrhaging 3 days after PDT [14] occurred in 1 patient with T4/N2 adenocarcinoma of the distal third of the esophagus. Despite blood transfusions, the patient died 2 days later. Postmortem examination revealed transmural necrosis of the esophageal wall with concurrent mediastinitis and erosion of the thoracic aorta as the cause of death. In 1 patient with T4 carcinoma, spontaneous perforation of the distal esophagus with esophagomediastinopleural fistula and concurrent pleural empyema developed 5 months after PDT, brachyradiotherapy, and external-beam irradiation. The patient died 1 day after admission. Four patients with a T4 carcinoma in the proximal and middle third of the esophagus had development of a tracheoesophageal or tracheobronchial fistula [14]; this occurred 4 to 7 months after PDT and brachyradiotherapy in 2 patients and after PDT, brachytherapy, and external-beam irradiation in 2 patients. The fistulas were treated by implanting self-expandable stents (Microvasive; Boston Scientific Corp, Watertown, MA) [13–15]. Additional tracheotomy became necessary in 2 patients because extensive tumor growth in the trachea caused by respiratory insufficiency. All complications occurred in patients with prior T4 carcinoma and transmural necrosis several months after endoluminal treatment.

In conclusion, major complications occurred in 9.2% (11 of 119) of patients. The 30-day mortality rate was 1.7% (2 of 119).

Minor complications
Because of strictures, dilation was necessary in 4 patients after PDT [16] and in 45 patients after iridium 192 afterloading therapy [17] and were done on an outpatient basis. After PDT, 28 patients reported odynophagia for at least 2 to 5 days. Delirium tremens occurred in 2 patients. In 1 patient, pneumonia developed in the right lower lobe.

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
Brachytherapy, external-beam irradiation, Nd:YAG laser tumor obliteration, and intubation are well-accepted methods to treat advanced esophageal carcinoma. Photodynamic therapy has been approved for use in the United States, Finland, and the United Kingdom, but in many other countries, it is still an experimental treatment. Only a few studies [14, 16] examining the combination of PDT and radiotherapy were found in the literature, and in these reports, PDT was used only after radiation treatment failed. We are aware of no study that discusses the use of PDT followed by irradiation in a stepwise procedure.

We decided to combine PDT with radiotherapy to better the results obtained with irradiation alone. McCaughan and colleagues [16], noted that hard tumors become soft after PDT, and in our experience [17], irradiated tissue becomes hard after brachyradiotherapy, and there is a high incidence of postirradiation stenosis. We decided to use PDT as the first step followed by radiotherapy as a possible combination to prevent postirradiation stenosis and restore the gastroesophageal passage with acceptable mortality and morbidity. Our hypothesis was verified by the fact that we observed a lower rate of postirradiation stenosis in our patients treated by PDT and brachyradiotherapy in a stepwise procedure compared with patients treated by brachyradiotherapy alone (9.1% and 60%, respectively).

Endoluminal tumoricidal treatment of patients with advanced esophageal carcinoma is associated with a high complication rate [13, 14]. Despite the absence of signs of tracheobronchial infiltration at staging bronchoscopy, we found an increased risk of esophagorespiratory tract fistulas after combined PDT and brachyradiotherapy for T4 carcinoma of the proximal third and of the middle third of the esophagus. All fistulas occurred several months after combined PDT and irradiation. However, in the case of advanced esophageal carcinoma, it is difficult to distinguish between tumor-related and treatment-related complications, especially if these develop several months after treatment. Nevertheless, we believe that there is a primary connection between the aggressive palliative treatment regimen and the increasing number of esophagorespiratory tract fistulas that occurred in our patients. It is of note that during the same observation period, we found no such fistula in patients with T4 carcinoma of the proximal third and middle third of the esophagus treated by HDR brachyradiotherapy alone. These observations were confirmed at postmortem examination when necrotic tissue but no active tumor tissue could be found at the prior tumor site.

Therefore, one should be wary of using an aggressive treatment regimen in patients with T4 carcinoma of the proximal and middle third of the esophagus. Especially, when there is initial tracheal or bronchial tumor involvement at staging bronchoscopy, we do not recommend combined PDT and brachyradiotherapy because of the very high risk of fistula formation [14, 16]. In contrast, esophageal perforation immediately after brachyradiotherapy was seen in 3 of our patients (in 2 immediately after irradiation and in 1 after dilation necessitated by postirradiation stenosis) and was due to technical difficulties. All major complications in our series occurred in patients with T4 carcinoma. However, the overall incidences of perforation and fistula formation in our series were no greater than those reported for other treatment regimens [3, 4, 6].

In patients unable to eat a regular meal, dysphagia is the symptom with the most severe impact on quality of life. In patients with an incurable disease and a short life expectancy, a decrease in dysphagia automatically results in a better quality of life because the patients are able to stay at home and continue their social life. In general, many factors together determine quality of life. However, the compliance of patients using self-completion questionnaires is often poor [18].

Statistical analysis revealed PDT to be as the most significant treatment for increasing luminal diameter and decreasing dysphagia. This finding, however, is biased by the fact that Nd:YAG laser obliteration [19] was used only in patients with severe stenosis (< 5 mm) to facilitate the passage of endoscopes at least 7 mm in diameter for PDT. Nevertheless, the decrease in dysphagia and the increase in luminal diameter after PDT justify the more frequent treatment sessions compared with HDR brachyradiotherapy alone. In patients with severe stenosis (< 5 mm) and the need of Nd:YAG laser obliteration, an additional one to two sessions were necessary. Treatment costs rise with the number of treatment sessions and the kind of treatment (PDT is more expensive than Nd:YAG laser therapy). In general, it depends on the national health system which treatment regimen is available for patients with an incurable disease.

	References

Top Abstract Introduction Material and methods Results Comment References

 

1. Oliver S.E., Robertson C.S., Logan R.F.A. Esophageal cancer. Br J Surg 1992;79:1321-1325.[Medline]
2. Fok M., Sham J.S., Chay D., Chung S.W.K., Wong J. Postoperative radiotherapy for carcinoma of the esophagus. Surgery 1993;113:138-147.[Medline]
3. Sur R.K., Singh D.P., Sharma S.C., et al. Radiation therapy of esophageal cancer. Int J Radiat Oncol Biol Phys 1992;22:1043-1046.[Medline]
4. Hareyama M., Nishio M., Kagami Y., Narimatsu N., Saito A., Sakurai T. Intracavitary brachytherapy combined with external-beam irradiation for squamous cell carcinoma of the thoracic esophagus. Int J Radiat Oncol Biol Phys 1992;24:235-240.[Medline]
5. Rutgeerts P., Vantrappen G., Broeckaert L., et al. Palliative Nd:YAG laser therapy for cancer of the esophagus and gastroesophageal junction. Gastrointest Endosc 1988;34:87-90.[Medline]
6. Cusumano A., Ruol A., Segalin A., et al. Push-through intubation. Ann Thorac Surg 1992;53:1010-1014.[Abstract]
7. Sakamoto T., Kotah H., Shimizu T. Clinical results of treatment of advanced esophageal carcinoma with hyperthermia in combination with chemotherapy. Chest 1997;112:1487-1493.[Abstract/Free Full Text]
8. Sibille A., Lambert R., Souquet J., Sabben G., Descos F. Long-term survival after photodynamic therapy for esophageal carcinoma. Gastroenterology 1995;108:337-344.[Medline]
9. Karanov S., Shopova M., Getov H. Photodynamic therapy in gastrointestinal cancer. Lasers Surg Med 1991;11:395-408.[Medline]
10. McCaughan J.S., Jr Photodynamic therapy versus Nd:YAG laser treatment of endobronchial or esophageal malignancies. In: Spinelli P., Dal Fante M., Marchesini R., eds. Photodynamic therapy and biomedical lasers. New York: Elsevier, 1992:23-36.
11. Dougherty T.J., Kaufman J.E., Goldfarb A., et al. Photoradiation therapy for the treatment of malignant tumors. Cancer Res 1978;38:2628-2635.[Abstract/Free Full Text]
12. Hermanek P., Sobin L.H. TNM classification of malignant tumours, 4th ed. Berlin: Springer Verlag, 1987:42.
13. Hishikawa Y., Tanaka S., Miura T. Esophageal fistula associated with intracavitary irradiation for esophageal carcinoma. Radiology 1986;159:549-551.[Abstract/Free Full Text]
14. Maier A., Pinter H., Friehs G.B., Renner H., Smolle-Jüttner F.M. Self-expandable coated stent after intraluminal treatment of esophageal cancer. Ann Thorac Surg 1999;67:781-784.[Abstract/Free Full Text]
15. Wong K., Goldstraw P. Role of covered esophageal stents in malignant esophagorespiratory fistula. Ann Thorac Surg 1995;60:199-200.[Abstract/Free Full Text]
16. McCaughan J.S., Jr, Ellison E.C., Guy J.T., et al. Photodynamic therapy for esophageal malignancy. Ann Thorac Surg 1996;62:1005-1010.[Abstract/Free Full Text]
17. Hishikawa Y., Kamikonya N., Tanaka S., Miura T. Esophageal stricture following high-dose-rate intracavitary irradiation for esophageal cancer. Radiology 1986;159:715-716.[Abstract/Free Full Text]
18. Blazeby J.M., Williams M.H., Alderson D., Farndon J.R. Observer variation in assessment of quality of life in patients with esophageal cancer. Br J Surg 1995;82:1200-1203.[Medline]
19. Heier S.K., Rothman K.A., Heier L.M., Rosenthal W.S. Photodynamic therapy for obstructing esophageal cancer. Gastroenterology 1995;109:63-72.[Medline]

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