Photodiagnosis and Photodynamic Therapy (2004) 1, 65—74
Photodynamic therapy in the esophagus Shou-jiang Tang, Fellow, MD, Norman E. Marcon, Professor, MD* Center for Therapeutic Endoscopy and Endoscopic Oncology, St. Michael’s Hospital, University of Toronto, Toronto, Ont., Canada M5B 1W8
KEYWORDS Photodynamic therapy; Esophagus; Dysplasia; Porfimer sodium; ALA; BPD-MA
Summary Photodynamic therapy (PDT) involves in situ photo-activation of photosensitizers by light at appropriate wavelength, generating highly active singlet oxygen and free radicals. For esophageal mucosal dysplasia such as high-grade dysplasia or intramucosal cancer, curative endoluminal therapy including PDT is now a reality. We review the role of PDT in the esophagus for the past two decades. The light for PDT can be delivered endoluminally freehand by cylindrical diffusers, via inflatable balloon stabilizers or microlens fibers. Porfimer sodium (Photofrin® ) is the only approved photosensitizer for PDT in the esophagus in North America, Europe and Japan. In addition, 5-aminolaevulinic acid (ALA), m-tetra(hydroxyphenyl)chlorin (m-THPC) and benzoporphyrin derivative monoacid ring A (BPD-MA) are other photosensitizers are being evaluated. More randomized clinical trials with long term follow up data are needed to further establish the role of PDT and other endoluminal ablative therapies either on their own or in combination to demonstrate survival benefits, quality of life advantages and cost-effectiveness. Changes in light delivery, timing, dosimetry and new endoscopic devices are needed to possibly improve all aspects of effectiveness. PDT was used mainly for palliation of advanced obstructing cancer of the esophagus at the gastrointestinal junction. More recently, because of the rising detection of the high-grade dysplasia in Barrett’s esophagus, a curative role of PDT in being realized. © 2004 Elsevier B.V. All rights reserved.
Introduction Photodynamic therapy (PDT) involves in situ photo-activation of photosensitizing drugs by light at appropriate wavelength, generating highly active and short-lived oxygen derived species. These cytotoxic species, including singlet oxygen and free radicals, induct direct oxidative damage to cellular organelles, destruction of microvasculature and promotion of apoptosis. PDT may also impart an immunological effect as well as a local apoptotic effect. PDT effect is determined by photosensitizer absorption spectrum, the light wavelength
∗ Corresponding author. Tel.: +1-416-864-3092; fax: +1-416-864-5993. E-mail address: [email protected] (N.E. Marcon).
and light dose, selective tissue localization of the photosensitizer, the biological response of tissue and the presence of competing chromophores. Although esophageal cancer accounts for 1% of all cancers, it surprisingly represents 12% of all cancer deaths and is the seventh leading cause of cancer death worldwide. The disease is often quite advanced before patient develops symptoms of dysphagia. The prognosis is very poor once the tumor has extended beyond the esophageal wall with 5-year survival rates of 5—10%. For locally advanced cancer, surgical esophagectomy is appropriate in operable patients. In the Western world, esophageal adenocarcinoma has become one of the most rapidly rising incidences of any malignancy over the past 30 years. Barrett’s esophagus is associated with increased risk of esophageal adenocarcinoma [1,2]. It is characterized by the
1572-1000/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(04)00010-9
66 replacement of normal squamous esophageal mucosa by specialized intestinal type columnar mucosa (Fig. 2A). Gastroesophageal reflux of acid, bile acids and possible other compounds are thought to play a significant role in the pathogenesis of Barrett’s epithelium. It is hypothesized that injury heals through a metaplastic process in which an abnormal columnar epithelium replaces the injured squamous epithelium [1,2]. Barrett’s esophagus can be found in 1—1.6% of general population in the United States [3]. It is estimated that about 5% of patients with Barrett’s esophagus will progress to cancer, a 40—100% fold increase compared with that of the background population. There appears to have a familial association among Barrett’s patients. The increasing use of endoscopic screening and surveillance programs can expect to encounter more patients with Barrett’s dysplasia and early cancer. For esophageal mucosal dysplasia such as high-grade dysplasia or intramucosal cancer, curative endoluminal therapy is now a reality [4]. Early and appropriate endoscopic interventions with PDT and/or endoscopic mucosal resection (EMR) may lead to a better prognosis or cure in well staged patients with either Barrett’s or squamous dysplasia providing the muscularis mucosae is intact and the submucos is uninvolved. The goal is provide survival benefit comparable to that of surgical esophagectomy with less morbidity and is more cost-effective. McCaughan et al. in 1984 pioneered PDT in the esophagus [5]. He applied PDT to palliate seven patients with advanced esophageal cancers including adenocarcinoma, squamous carcinoma and melanoma with good response. In the past two decades, there has been an exponential growth in the research and clinical application of PDT in the esophagus and other organs in the human gastrointestinal tract [6—8]. We begin with description of the components of PDT such as light sources, light application or delivery systems, photosensitizers and dosimetry.
Light sources and application systems For photosensitizers used in esophageal application, the optimal wavelengths fall in the range of 530—700 nm (413 nm-blue light, 514 nm-green light, 630—635 nm-red light: Photofrin/630 nm; ALA/630 and 635 nm; Forscan/650 nm) and laser has become the preferred light source due to its monochromatic nature. Red light (630 nm) has mostly been used in clinical esophageal PDT (Photofrin). The exciting light is delivered via an optical fiber that is passed through the accessory channel of the en-
S.-j. Tang, N.E. Marcon doscope [9]. The original light source in clinical PDT was an argon dye-laser based system and is expensive, require water-cooling, special electrical transformers, and often frequent adjustments. Potassium titanyl phosphate (KTP)-pumped dye laser systems can be more powerful, provide the thermal options of laser therapy as well as PDT (Laserscope, San Jose, CA, USA). Now compact diode-laser based light systems (Diomed, Cambridge, UK) are commercially available and they are somewhat cheaper, do not require water-cooling or special transformers (Fig. 1A). The downside is that currently they have limited power output that may require longer treatment time and emit light of a single wavelength and are not tunable. The light for PDT can be delivered endoluminally by cylindrical diffusers, via inflatable balloon applicator stabilizers or microlens fibers. Cylindrical diffusers: Cylindrical diffusers are the most widely used light application devices in the esophageal PDT. The optical fiber can be placed either ‘‘freehand’’ in the lumen or by directly inserting short (1 cm) diffuser tip into the tumor bulk. The length of the diffusing tips range from 1 to 7 cm (Figs. 1B and 2B). Microlens fibers: The microlens fiber can focus light on a circular area of lesion. The distance between the fiber tip and the target lesion dedicates the size of the circular area. Microlens fiber is seldom used the GI tract because of difficulty in holding the fiber in place such as in the antrum, gastric body or other capacious parts of GI tract. Balloon applicators: The tubular nature of the esophagus, its intrinsic peristalsis and respective gastric cardiac movement can interfere with even distribution of light dose to the lesional surface. Therefore, a balloon-stabilizing device is available and helps to unfold the esophagus and stabilize the esophagus during PDT [10,11] (Fig. 1C). When applying PDT within a hallow organ as the esophagus, due to the scattering and reflection, the actually delivered fluence rate (light dose) can vary. In one study, when using diffusing balloons, the actual fluence rate measured was 1.5—3.9 times higher than the primary fluence rate for 630 nm [12]. The actual fluence rate measured changed (increased, unchanged or decreased) with patient’s coughing, movement, esophageal spasms and redness of the esophagus. This factor could lead to over or under treatment of certain areas in the esophagus. Further studies are needed to define the role of these interfering factors and their clinical importance. These stabilizing balloons are passed over a semistiff guidewire and its position is monitored under direct endoscopic visualization. The windowcentering balloon (Wilson-Cook, Winston-Salem,
Photodynamic therapy in the esophagus
67
Figure 1 (A) Compact diode-laser based light system for clinical PDT (Diomed® , Cambridge, UK). (B) Cylindrical diffusers of variable length. (C) 360◦ windowed esophageal centering balloon (Wilson-Cook® , Winston-Salem, NC, USA).
Figure 2 Endoscopic views showing various applications of Photofrin-PDT in the esophagus and its potential development of stricture. (A) Barrett’s high-grade dysplasia in the distal esophagus. (B) PDT with a cylindrical diffuser for ablating this high-grade dysplasia. (C) Adequate tissue injury at 48 h after PDT ablation. (D) Successful ablation with distal esophagus re-epithelialized with squamous mucosa. (E) Benign stricture developed in another patient after PDT. The stricture is usually managed by endoscopic esophageal dilatation. (F) Adequate tissue injury at 48 h after PDT for cancer palliation.
68 NC, USA) is a balloon with a central channel to hold the optical fiber (Fig. 1C). The balloon delivers light in 360◦ . Both ends of the balloon are blackened to minimize light scattering. Window size ranges from 3 to 7 cm with a 5—9 cm diffusing fiber inside. The balloon window length is selected to treat all dysplasia and Barrett’s mucosa with 0.5—1 cm of the normal tissue margin. Selecting proper balloon size is crucial [13—15]. The balloon should be in gentle contact with the wall. Excessively distended large diameter balloon can reduce PDT effect by reducing esophageal mucosal blood flow and oxygen supply [13]. On the other hand, a balloon of inadequate diameter (7 cm) in one setting, testing of 10 or 12 cm long windowed balloon is contemplated. When two balloons directed application are needed at one site, there is inevitable overlap leading potentially more strictures at the overlap site. If the lesion is not circumferential, there is a theoretical advantage of using a 180◦ or 240◦ windowed cylindrical balloon to potentially avoid circumferential irradiation of esophageal wall hoping to reduce the development of stricture. There are no incomplete windowed balloons commercially available.
Photosensitizers Porfimer sodium (Photofrin® ) Hematoporphyrin derivative is a complex mixture of porphyrins and was the first clinical photosensitizer in the esophagus. When refined to an oligomeric mixture with a predominance of dihematoporphyrin ethers and esters, it has become commercially available as porfimer sodium (Photofrin® , Axcan Pharma, Montreal, Canada). This photosensitizer is given intravenously and is the only photosensitizer approved for PDT in the esophagus in North America, Europe and Japan. Although the highest absorption coefficient of Photofrin is at 514 nm, the tissue penetration therefore is very minimal to achieve the adequate therapeutic effect. Although Photofrin absorbs relative weak at 630 nm, the clinical response is best with depth of penetration up to 3—4 mm. The standard dose is 2 mg/kg (reconstituted in 5% glucose prior to use) and is given 48 h prior to the illumination. Photofrin retains in the skin for up to 2 months resulting in cutaneous photosensitivity to sunlight. If sunlight precautions are not practiced, severe sunburn can result early on. This can be reduced by controlled gradual sunlight exposure
S.-j. Tang, N.E. Marcon (photobleaching). Photofrin has less selective drug tumor-to-normal tissue ratio. Despite these shortcomings, Photofrin induced PDT (Photofrin-PDT) has been widely used in clinical practice for ablating dysplasia and early cancer in both Barrett’s and squamous esophagus, and palliating advanced cancers [8,16].
5-Aminolaevulinic acid (ALA) ALA (Levulan® , DUSA Pharmaceuticals Inc., Wilmington, MA, USA) is a second-generation photosensitizer and is taken orally [17]. ALA is a natural pro-drug generating protoporphyrin IX (PPIX) as part of hemoglobin synthesis, an endogenous photosensitizer that is activated at 630—635 nm in vivo. Porphobilinogen deaminase is rate-limiting enzyme in PPIX formation whereas ferrochelatase converts PPIX into heme by chelation of ferrous iron into PPIX. PPIX accumulates mainly in the epithelium and to a lesser degree to the lamina propria or submucosa, accounting for the limited depth tissue injury (
Photodynamic therapy in the esophagus Shou-jiang Tang, Fellow, MD, Norman E. Marcon, Professor, MD* Center for Therapeutic Endoscopy and Endoscopic Oncology, St. Michael’s Hospital, University of Toronto, Toronto, Ont., Canada M5B 1W8
KEYWORDS Photodynamic therapy; Esophagus; Dysplasia; Porfimer sodium; ALA; BPD-MA
Summary Photodynamic therapy (PDT) involves in situ photo-activation of photosensitizers by light at appropriate wavelength, generating highly active singlet oxygen and free radicals. For esophageal mucosal dysplasia such as high-grade dysplasia or intramucosal cancer, curative endoluminal therapy including PDT is now a reality. We review the role of PDT in the esophagus for the past two decades. The light for PDT can be delivered endoluminally freehand by cylindrical diffusers, via inflatable balloon stabilizers or microlens fibers. Porfimer sodium (Photofrin® ) is the only approved photosensitizer for PDT in the esophagus in North America, Europe and Japan. In addition, 5-aminolaevulinic acid (ALA), m-tetra(hydroxyphenyl)chlorin (m-THPC) and benzoporphyrin derivative monoacid ring A (BPD-MA) are other photosensitizers are being evaluated. More randomized clinical trials with long term follow up data are needed to further establish the role of PDT and other endoluminal ablative therapies either on their own or in combination to demonstrate survival benefits, quality of life advantages and cost-effectiveness. Changes in light delivery, timing, dosimetry and new endoscopic devices are needed to possibly improve all aspects of effectiveness. PDT was used mainly for palliation of advanced obstructing cancer of the esophagus at the gastrointestinal junction. More recently, because of the rising detection of the high-grade dysplasia in Barrett’s esophagus, a curative role of PDT in being realized. © 2004 Elsevier B.V. All rights reserved.
Introduction Photodynamic therapy (PDT) involves in situ photo-activation of photosensitizing drugs by light at appropriate wavelength, generating highly active and short-lived oxygen derived species. These cytotoxic species, including singlet oxygen and free radicals, induct direct oxidative damage to cellular organelles, destruction of microvasculature and promotion of apoptosis. PDT may also impart an immunological effect as well as a local apoptotic effect. PDT effect is determined by photosensitizer absorption spectrum, the light wavelength
∗ Corresponding author. Tel.: +1-416-864-3092; fax: +1-416-864-5993. E-mail address: [email protected] (N.E. Marcon).
and light dose, selective tissue localization of the photosensitizer, the biological response of tissue and the presence of competing chromophores. Although esophageal cancer accounts for 1% of all cancers, it surprisingly represents 12% of all cancer deaths and is the seventh leading cause of cancer death worldwide. The disease is often quite advanced before patient develops symptoms of dysphagia. The prognosis is very poor once the tumor has extended beyond the esophageal wall with 5-year survival rates of 5—10%. For locally advanced cancer, surgical esophagectomy is appropriate in operable patients. In the Western world, esophageal adenocarcinoma has become one of the most rapidly rising incidences of any malignancy over the past 30 years. Barrett’s esophagus is associated with increased risk of esophageal adenocarcinoma [1,2]. It is characterized by the
1572-1000/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/S1572-1000(04)00010-9
66 replacement of normal squamous esophageal mucosa by specialized intestinal type columnar mucosa (Fig. 2A). Gastroesophageal reflux of acid, bile acids and possible other compounds are thought to play a significant role in the pathogenesis of Barrett’s epithelium. It is hypothesized that injury heals through a metaplastic process in which an abnormal columnar epithelium replaces the injured squamous epithelium [1,2]. Barrett’s esophagus can be found in 1—1.6% of general population in the United States [3]. It is estimated that about 5% of patients with Barrett’s esophagus will progress to cancer, a 40—100% fold increase compared with that of the background population. There appears to have a familial association among Barrett’s patients. The increasing use of endoscopic screening and surveillance programs can expect to encounter more patients with Barrett’s dysplasia and early cancer. For esophageal mucosal dysplasia such as high-grade dysplasia or intramucosal cancer, curative endoluminal therapy is now a reality [4]. Early and appropriate endoscopic interventions with PDT and/or endoscopic mucosal resection (EMR) may lead to a better prognosis or cure in well staged patients with either Barrett’s or squamous dysplasia providing the muscularis mucosae is intact and the submucos is uninvolved. The goal is provide survival benefit comparable to that of surgical esophagectomy with less morbidity and is more cost-effective. McCaughan et al. in 1984 pioneered PDT in the esophagus [5]. He applied PDT to palliate seven patients with advanced esophageal cancers including adenocarcinoma, squamous carcinoma and melanoma with good response. In the past two decades, there has been an exponential growth in the research and clinical application of PDT in the esophagus and other organs in the human gastrointestinal tract [6—8]. We begin with description of the components of PDT such as light sources, light application or delivery systems, photosensitizers and dosimetry.
Light sources and application systems For photosensitizers used in esophageal application, the optimal wavelengths fall in the range of 530—700 nm (413 nm-blue light, 514 nm-green light, 630—635 nm-red light: Photofrin/630 nm; ALA/630 and 635 nm; Forscan/650 nm) and laser has become the preferred light source due to its monochromatic nature. Red light (630 nm) has mostly been used in clinical esophageal PDT (Photofrin). The exciting light is delivered via an optical fiber that is passed through the accessory channel of the en-
S.-j. Tang, N.E. Marcon doscope [9]. The original light source in clinical PDT was an argon dye-laser based system and is expensive, require water-cooling, special electrical transformers, and often frequent adjustments. Potassium titanyl phosphate (KTP)-pumped dye laser systems can be more powerful, provide the thermal options of laser therapy as well as PDT (Laserscope, San Jose, CA, USA). Now compact diode-laser based light systems (Diomed, Cambridge, UK) are commercially available and they are somewhat cheaper, do not require water-cooling or special transformers (Fig. 1A). The downside is that currently they have limited power output that may require longer treatment time and emit light of a single wavelength and are not tunable. The light for PDT can be delivered endoluminally by cylindrical diffusers, via inflatable balloon applicator stabilizers or microlens fibers. Cylindrical diffusers: Cylindrical diffusers are the most widely used light application devices in the esophageal PDT. The optical fiber can be placed either ‘‘freehand’’ in the lumen or by directly inserting short (1 cm) diffuser tip into the tumor bulk. The length of the diffusing tips range from 1 to 7 cm (Figs. 1B and 2B). Microlens fibers: The microlens fiber can focus light on a circular area of lesion. The distance between the fiber tip and the target lesion dedicates the size of the circular area. Microlens fiber is seldom used the GI tract because of difficulty in holding the fiber in place such as in the antrum, gastric body or other capacious parts of GI tract. Balloon applicators: The tubular nature of the esophagus, its intrinsic peristalsis and respective gastric cardiac movement can interfere with even distribution of light dose to the lesional surface. Therefore, a balloon-stabilizing device is available and helps to unfold the esophagus and stabilize the esophagus during PDT [10,11] (Fig. 1C). When applying PDT within a hallow organ as the esophagus, due to the scattering and reflection, the actually delivered fluence rate (light dose) can vary. In one study, when using diffusing balloons, the actual fluence rate measured was 1.5—3.9 times higher than the primary fluence rate for 630 nm [12]. The actual fluence rate measured changed (increased, unchanged or decreased) with patient’s coughing, movement, esophageal spasms and redness of the esophagus. This factor could lead to over or under treatment of certain areas in the esophagus. Further studies are needed to define the role of these interfering factors and their clinical importance. These stabilizing balloons are passed over a semistiff guidewire and its position is monitored under direct endoscopic visualization. The windowcentering balloon (Wilson-Cook, Winston-Salem,
Photodynamic therapy in the esophagus
67
Figure 1 (A) Compact diode-laser based light system for clinical PDT (Diomed® , Cambridge, UK). (B) Cylindrical diffusers of variable length. (C) 360◦ windowed esophageal centering balloon (Wilson-Cook® , Winston-Salem, NC, USA).
Figure 2 Endoscopic views showing various applications of Photofrin-PDT in the esophagus and its potential development of stricture. (A) Barrett’s high-grade dysplasia in the distal esophagus. (B) PDT with a cylindrical diffuser for ablating this high-grade dysplasia. (C) Adequate tissue injury at 48 h after PDT ablation. (D) Successful ablation with distal esophagus re-epithelialized with squamous mucosa. (E) Benign stricture developed in another patient after PDT. The stricture is usually managed by endoscopic esophageal dilatation. (F) Adequate tissue injury at 48 h after PDT for cancer palliation.
68 NC, USA) is a balloon with a central channel to hold the optical fiber (Fig. 1C). The balloon delivers light in 360◦ . Both ends of the balloon are blackened to minimize light scattering. Window size ranges from 3 to 7 cm with a 5—9 cm diffusing fiber inside. The balloon window length is selected to treat all dysplasia and Barrett’s mucosa with 0.5—1 cm of the normal tissue margin. Selecting proper balloon size is crucial [13—15]. The balloon should be in gentle contact with the wall. Excessively distended large diameter balloon can reduce PDT effect by reducing esophageal mucosal blood flow and oxygen supply [13]. On the other hand, a balloon of inadequate diameter (7 cm) in one setting, testing of 10 or 12 cm long windowed balloon is contemplated. When two balloons directed application are needed at one site, there is inevitable overlap leading potentially more strictures at the overlap site. If the lesion is not circumferential, there is a theoretical advantage of using a 180◦ or 240◦ windowed cylindrical balloon to potentially avoid circumferential irradiation of esophageal wall hoping to reduce the development of stricture. There are no incomplete windowed balloons commercially available.
Photosensitizers Porfimer sodium (Photofrin® ) Hematoporphyrin derivative is a complex mixture of porphyrins and was the first clinical photosensitizer in the esophagus. When refined to an oligomeric mixture with a predominance of dihematoporphyrin ethers and esters, it has become commercially available as porfimer sodium (Photofrin® , Axcan Pharma, Montreal, Canada). This photosensitizer is given intravenously and is the only photosensitizer approved for PDT in the esophagus in North America, Europe and Japan. Although the highest absorption coefficient of Photofrin is at 514 nm, the tissue penetration therefore is very minimal to achieve the adequate therapeutic effect. Although Photofrin absorbs relative weak at 630 nm, the clinical response is best with depth of penetration up to 3—4 mm. The standard dose is 2 mg/kg (reconstituted in 5% glucose prior to use) and is given 48 h prior to the illumination. Photofrin retains in the skin for up to 2 months resulting in cutaneous photosensitivity to sunlight. If sunlight precautions are not practiced, severe sunburn can result early on. This can be reduced by controlled gradual sunlight exposure
S.-j. Tang, N.E. Marcon (photobleaching). Photofrin has less selective drug tumor-to-normal tissue ratio. Despite these shortcomings, Photofrin induced PDT (Photofrin-PDT) has been widely used in clinical practice for ablating dysplasia and early cancer in both Barrett’s and squamous esophagus, and palliating advanced cancers [8,16].
5-Aminolaevulinic acid (ALA) ALA (Levulan® , DUSA Pharmaceuticals Inc., Wilmington, MA, USA) is a second-generation photosensitizer and is taken orally [17]. ALA is a natural pro-drug generating protoporphyrin IX (PPIX) as part of hemoglobin synthesis, an endogenous photosensitizer that is activated at 630—635 nm in vivo. Porphobilinogen deaminase is rate-limiting enzyme in PPIX formation whereas ferrochelatase converts PPIX into heme by chelation of ferrous iron into PPIX. PPIX accumulates mainly in the epithelium and to a lesser degree to the lamina propria or submucosa, accounting for the limited depth tissue injury (
