Photodynamic therapy (PDT) is a drug and device therapy using photosensitizer drugs activated by laser light for mucosal ablation. Porfimer sodium PDT has been used extensively with proven long-term efficacy and durability for the ablation of Barrett esophagus and high-grade dysplasia. and early esophageal adenocarcinoma. However, continued use is hampered by an associated stricture risk and prolonged photosensitivity (4–6 weeks). Promising single-center European studies using other forms of PDT, such as aminolevulinic acid PDT, have not been replicated elsewhere, limiting the widespread use of other forms of PDT. Future use of PDT in esophageal disease depends on the development of improved dosimetry and patient selection to optimize treatment outcomes, while minimizing adverse events and complications.
Although the photodynamic effect has been known since ancient times, the modern use of photodynamic therapy (PDT) was not discovered until the early 20th century. Dougherty and colleagues were the first to describe the response of malignancies to PDT, using hematoporphyrin derivative (HpD) exposure to red light.
The US Food and Drug Administration (FDA) did not approve the use of porfimer sodium PDT (Ps-PDT) for the palliation of patients with obstructing esophagus cancer until 1995. In 2003, Ps-PDT was granted regulatory approval as an alternative to esophagectomy for patients with Barrett esophagus and high-grade dysplasia (BE-HGD).
PDT is a complex treatment, and several components are necessary to achieve a tumor-destructive effect. The photosensitizer accumulates in malignant and premalignant tissue before light activation therapy. The most common photosensitizer is porfimer sodium, which is injected at a dose of 1.5 to 2 mg/kg 24 to 72 hours before the procedure. Other commonly used photosensitizers include m -tetrahydroxyphenyl chlorine (mTHPC) and aminolevulinic acid (ALA). Porfimer sodium is aromatically complex and becomes active when exposed to light at a wavelength of 630 nm. The excited molecules then react with oxygen, resulting in singlet oxygen and other reactive oxygen species, which leads to cell-membrane damage and ultimately apoptosis. The depth of invasion at wavelength of 630 nm is estimated to be 5 to 6 mm, depending on tissue blood flow and oxygen levels. The patient returns for upper endoscopy, using a diffusing light fiber placed alongside the targeted tissue, within an estimated 48 hours of injecting the photosensitizer. Patients may subsequently return within 24 to 48 hours for repeated laser light application to make sure the targeted area is completely treated.
This review of PDT focuses on its role in the treatment of esophageal dysplasia and carcinoma, including some of the best tested and earliest clinical applications to receive regulatory approval. Initially, most of this research focused on the use of Ps-PDT in patients with advanced esophageal cancer, leading to regulatory approvals in Japan, North America, United Kingdom, and mainland Europe. Later, multicenter studies examined the use of Ps-PDT in BE-HGD patients, including a prospective, randomized, controlled international trial that demonstrated a significantly reduced rate of development of invasive carcinoma. These studies, and many others, established the importance of Ps-PDT in the treatment of esophageal dysplasia and neoplasia and supported the development and clinical use of other photosensitizers ( Table 1 ).
| Class | Photosensitizer | Treatment Wavelength (λ, nm) | Diagnostic Fluorescence Wavelength (λ, nm) | Comments |
|---|---|---|---|---|
| Porphyrins | Porfimer sodium; also HpD; DHE | 630 | 665–690 | Porfimer sodium excellent red light tissue penetration with risk of stricture and prolonged skin sensitivity (Photofrin; also Photosan) |
| 5-ALA, a precursor of endogenous porphyrins | 630–635 | 525, 665–690 | Limited tissue penetration (≤2 mm); less photosensitivity (Levulan; Metvix) | |
| Chlorins | mTHPC; temoporfin | 650–660 (red) 514 (green) | 525 | Highly selective, potent 514 (green) compound suitable for less powerful light sources. Approved in European Union, Norway and Iceland (Foscan; Biolitec Pharma) |
| Purpurins (porphyrin macromolecules) | Mono- l -aspartyl chlorine e6 (NPe6; talaporfin or LS11); tin-etio-purpurin (SnEt2) | 660–665 | 675 | Phase III study using LS11 for hepatoma activated with light emitting diode (LED) (Light Sciences Oncology, Bellevue, WA, USA ) |
| Phthalocyanine | Silicon phthalocyanine (Pc4); aluminum disulfonated phthalocyanine (AISPc); chloroaluminum phthalocyanine tetrasulfonate (AIPcS 4 ) | 675 | 610 | Limited phototoxicity and limited clinical information hydrophobic compounds that are difficult to purify. Selective tumor retention, minimal dark and cutaneous photosensitivity and excellent photodynamic activity are expected (Photosens) |
| Benzoporphyrins | Benzoporphyrin derivative (BPD); benzoporphyrin derivative monoacid (BPDMA); diethylene glycol benzoporphyrin derivative (Lemuteporfin) | 690 | 690 | Rapid tumor accumulation; transient limited skin photosensitivity and prominent vascular effects produced approval for use in macular degeneration (Visudyne); new diethylene glycol functionalized chlorine-type photosensitizer |
| Porphyrin-like compounds | Motexafin lutetium; lutetium texaphyrin | 730–740 | 730–740 | Rapid tissue uptake and clearance and tissue penetration; used for photochemical angioplasty (Antrin, Lutrin, Lu-Tex) |
| Pheophorbides: (tetrapyriolea) chlorophyll derivatives | 2-[1-Hexyloxyethyl]-2-devinyl-pyropheophorbide-a (HPPH) | 680 | 680 | Undergoing evaluations for use in esophageal, skin, and recurrent breast cancer (Photochlor) |
Key differences among these studies were patient selection, diagnostic evaluation, and PDT methods (ie, the photosensitizer, and its dose and route of administration). The light wavelength is particularly important since red light at 630 nm penetrates the esophageal tissue more deeply than green light at 532 nm. It is critical to note the other methods of ablation used in the study, and the rigor of postablation endoscopic surveillance. Although regulatory trials allow the use of PDT only, clinical series frequently use “focal” ablation methods (such as radiofrequency energy, argon plasma coagulation, or low-pressure liquid nitrogen cryotherapy) to remove small amounts of residual BE that persist after the initial PDT procedure. Regardless of treatment modality, it is recommended that all Barrett glandular metaplasia and dysplasia be removed to prevent the development or recurrence of invasive carcinoma.
BE-HGD and early cancer
The incidence of esophageal carcinoma, particularly in Western developed countries, has steadily increased in the past 50 years. BE is known to be the most important risk factor in the development of dysplasia and progression to esophageal adenocarcinoma. Endoscopic ablation therapy such as PDT is an ideal treatment for esophageal diseases, including BE, as gastrointestinal endoscopy provides ready access to the target mucosa for laser light application. Depending on the photosensitizer selected, the wavelength, and the dose of light energy used, PDT permits deep mucosal penetration of light energy to drive the photodynamic reaction with little risk of perforation, despite the relatively thin esophageal mucosa and its limited blood supply.
After the initial description of porphyrin-based PDT, HpD and dihematoporphyrin ether (DHE) activated with red light were the most commonly used photosensitizers. Subsequently, these drugs were better purified and characterized for commercial production in the form of porfimer sodium (Photofrin, Axcan Scandipharm, Mont-Saint-Hilaire, Quebec, Canada). Surgeons and gastrointestinal endoscopists used the prolonged mucosal retention of porfimer sodium, combined with red light activation, for deep mucosal and submucosal necrosis in the palliative treatment of advanced, obstructing lesions, and for the complete destruction of early cancers. The initial clinical studies were performed in patients with advanced carcinoma, and the results were compared with endoscopic palliation using stents or tumor ablation with thermal lasers. Improved endoscopic light delivery and dosimetry led to the use of Ps-PDT in patients with esophageal dysplasia (squamous dysplasia and BE with dysplasia).
Despite these advantages, porfimer sodium remains a first-generation drug that is relatively inefficient and produces prolonged photosensitivity, typically lasting 4 to 6 weeks. More recently developed photosensitizer agents include mTHPC (temoporfin, Foscan, Biolitec AG, Jena, Germany), a potent photosensitizing agent that requires lower drug and light doses and induces only 2 to 3 weeks of cutaneous photosensitivity. However, studies using mTHPC have been associated with higher stricture formation or full-thickness tissue necrosis and perforation. Another photosensitizing agent, ALA, is converted within the gut mucosa to its active form protoporphyrin IX (PpIX), and accumulates in the mucosal layer of the gut, which decreases the risk of stricture formation by sparing damage to the deeper esophageal wall and muscle layers. Commercially available preparations of ALA include aminolevulinic acid (Levulan, DUSA Pharmaceuticals, Wilmington, MA, USA), δ-aminolevulinic acid (medac GmbH, Wedel, Germany) and methyl aminolevulinate (Metvix, Photocure ASA, Oslo, Norway). Clinical experience with ALA in the esophagus has produced varied results, particularly in controlled trials performed with other forms of thermal ablation. 2-[1-Hexyloxyethyl]-2-devinyl-pyropheophorbide-a (HPPH, or Photochlor), a pheophorbide photosensitizer owned by the Roswell Park Cancer Institute. It features only mild photosensitivity at antitumor doses, but has not yet been widely tested in clinical studies. A more complete listing of photosensitizers used in esophageal PDT is given in Table 1 .
Porfimer sodium and HpD
Porfimer sodium is the most widely used photosensitizer in clinical practice and gastroenterological PDT. Porfimer sodium, an HpD, first received regulatory approval in Canada (1994), and then in the United States and Europe (1995), for the treatment of patients with advanced esophageal carcinoma. Overholt and colleagues reported the use of Ps-PDT in 84 BE patients who had low-grade dysplasia (LGD) or HGD and in 14 patients with T1 adenocarcinoma, with a mean follow-up of 19 months. To obtain improved light dosimetry and more uniform light-energy application, a balloon fiber centering device with mirrored caps was used to distend and flatten the esophageal mucosa. These investigators found that BE and LGD were eliminated in 92% of patients, and HGD was eliminated in 88% of patients. Complete elimination of Barrett glandular mucosa was noted in 43% of patients. In the group of patients with early cancer, successful endoscopic ablation was confirmed in 10 out of 14 cancers. The most common post-PDT complication was stricture development (34% of patients). It was often more common in those patients who had more than one session of PDT. Over the 19 months mean follow-up of this study, subsquamous epithelium was detected in 6% of patients, but there were no signs of dysplasia or cancer.
Several other centers with large clinical series subsequently reported similar results, with emphasis on the diagnostic evaluation of patients with esophageal dysplasia, including the use of endoscopic mucosal resection and endoscopic ultrasound with fine-needle aspiration for lymphadenopathy. Wolfsen and colleagues reviewed their experience treating 102 BE-HGD patients (n = 69) or early cancer patients (n = 33) with PDT, during a mean follow-up of 1.6 years. Fifty-six percent of patients had complete ablation of Barrett glandular epithelium, with a single session of Ps-PDT. Treatment failure was detected in four patients, with persistent HGD or carcinoma that required subsequent curative esophagectomy. A combined Mayo Clinic study at two independent sites enrolled 142 patients (60 patients at Jacksonville, Florida, and 72 patients at Rochester, Minnesota) for treatment with Ps-PDT, and followed these patients for a mean of 19 months. Complete elimination of BE was noted in 50% and 35% of patients, respectively. A balloon centering device was not used during the treatment sessions. Any residual disease detected after Ps-PDT was treated with argon plasma coagulation (APC), resulting in elimination of HGD in 100% and 80% of patients, respectively. The rates of post-PDT complications and stricture formation were 20% and 27%, respectively, rates comparable to those previously reported by Overholt. There was also a transient weight loss in patients who suffered from post-PDT chest discomfort or odynophagia. The number of patients who reported experiencing cutaneous photosensitivity was similar in the Minnesota and Florida patients. The rate of residual subsquamous epithelium was 0% and 4%, respectively, and 4% (n = 5) had residual dysplasia or neoplasm, ultimately requiring curative esophagectomy. In an effort to reduce the rate of stricture formation, a group of 60 patients with BE-HGD were treated with PDT alone or PDT combined with oral prednisone, but this strategy did not impact the rate of stricture formation. In the group given PDT alone, the stricture rate was 16% compared with 29% when PDT was combined with prednisone. Updated studies have compared the results of Ps-PDT alone and combined with endoscopic mucosal resection, and in a comparative cohort study with patients who have undergone esophagectomy. These studies found a similar overall survival in patients treated with endoscopic therapy using electromagnetic radiation and PS-PDT compared with surgery. The General Infirmary at Leeds, UK and the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, reported similar efficacy in patients with BE-HGD and esophageal carcinoma. Foroulis and Thorpe retrospectively evaluated the effectiveness of Ps-PDT in 31 patients with BE-HGD, 10 patients with intramucosal carcinoma, and 6 patients with endosonography stage T2 carcinoma, during a median follow-up of 10 months. In patients with HGD or intramucosal cancer, the treatment response was 80.9%. In patients with more advanced disease (T1b/T2), 2 of the 6 patients who were unfit for surgical resection had a complete response. Keeley and colleagues reviewed their experience using Ps-PDT in 50 patients treated for BE-HGD (13 patients) or locally advanced carcinoma, with a mean follow-up of 28 months. Sixteen patients also received treatment with chemoradiation. At last follow-up, 16 patients were alive and disease free, and 15 patients were receiving additional treatment for persistent or recurrent disease. The study concluded that Ps-PDT was potentially curative for patients with BE-HGD and superficial esophageal carcinomas, but not for more advanced disease.
The Photodynamic Therapy for Barrett’s Esophagus (PHO-BAR) trial was the first multicenter randomized control trial to evaluate the utility of Ps-PDT in patients with BE-HGD to be approved by the FDA. The study involved 30 sites, used an expert centralized pathology laboratory, and studied 208 patients randomized to PDT plus omeprazole or omeprazole alone (20 mg twice daily). After the initial treatment with Ps-PDT at 12 months, 41% of patients had complete remission of BE, and 72% had complete elimination of BE-HGD. This was statistically significant compared with the group with omeprazole alone. Treatment with Ps-PDT also decreased the rate of progression to adenocarcinoma from 28% in the drug-only group, to less than 10% in the PDT-plus-omeprazole group. These results were maintained at 2 years follow-up, resulting in the approval of Ps-PDT for treatment of BE-HGD in North America, United Kingdom, mainland Europe, and Japan. Recently, Overholt and colleagues reported a 5-year follow-up of the original study. They found persistent successful elimination of BE-HGD significantly more often in patients from the Ps-PDT-plus-omeprazole group (77%), compared with 39% of patients in the omeprazole-alone group. The secondary outcome of progressing to cancer remained significantly lower (15%) in the Ps-PDT-plus-omeprazole group compared with 29% in the omeprazole-alone group. Based on these large single-center studies with long-term follow-up and the results of this randomized controlled trial, porfimer sodium has become a first-line therapy for treating BE-HGD and superficial carcinoma at many referral centers. Although Ps-PDT has been shown to be efficacious in the treatment of BE-HGD, neosquamous overgrowth of Barrett mucosa may mask persistent dysplasia or cancer (so-called buried Barrett). Bronner and colleagues analyzed the histologic specimens of 33,658 biopsies from the PHO-BAR study and found no differences in squamous overgrowth between the 2 patient groups (those treated with acid-blocker therapy only and those treated with Ps-PDT). Long term studies found no risk of missing subsquamous dysplasia or carcinoma.
Stricture formation is the most common side effect with Ps-PDT. The pathophysiology of stricture development is not known. It has been postulated that the deep burn of Ps-PDT causes an inflammatory reaction, leading to a fibrotic response, resulting in stricture formation. Yachimski and colleagues retrospectively tried to identify pretreatment variables that may lead to postablation stricture development. One-hundred and sixteen patients had a total of 160 sessions of PDT, but only 16% of patients experienced stricture after their initial treatment. Patients having a second PDT treatment had overall stricture rate of 23%. Stricture development was not related to age, gender, body mass index, or prior endoscopic mucosal resection. Independent predictors of stricture development included patients with a longer segment, multiple PDT treatments, and evidence of intramucosal carcinoma before PDT. However, there is wide variation in Ps-PDT treatment parameters; a recent study compared pretreatment evaluation protocols, PDT light dosimetry, and follow-up evaluation protocols, in 10 large PDT referral centers in the United States.
Porfimer sodium and HpD
Porfimer sodium is the most widely used photosensitizer in clinical practice and gastroenterological PDT. Porfimer sodium, an HpD, first received regulatory approval in Canada (1994), and then in the United States and Europe (1995), for the treatment of patients with advanced esophageal carcinoma. Overholt and colleagues reported the use of Ps-PDT in 84 BE patients who had low-grade dysplasia (LGD) or HGD and in 14 patients with T1 adenocarcinoma, with a mean follow-up of 19 months. To obtain improved light dosimetry and more uniform light-energy application, a balloon fiber centering device with mirrored caps was used to distend and flatten the esophageal mucosa. These investigators found that BE and LGD were eliminated in 92% of patients, and HGD was eliminated in 88% of patients. Complete elimination of Barrett glandular mucosa was noted in 43% of patients. In the group of patients with early cancer, successful endoscopic ablation was confirmed in 10 out of 14 cancers. The most common post-PDT complication was stricture development (34% of patients). It was often more common in those patients who had more than one session of PDT. Over the 19 months mean follow-up of this study, subsquamous epithelium was detected in 6% of patients, but there were no signs of dysplasia or cancer.
Several other centers with large clinical series subsequently reported similar results, with emphasis on the diagnostic evaluation of patients with esophageal dysplasia, including the use of endoscopic mucosal resection and endoscopic ultrasound with fine-needle aspiration for lymphadenopathy. Wolfsen and colleagues reviewed their experience treating 102 BE-HGD patients (n = 69) or early cancer patients (n = 33) with PDT, during a mean follow-up of 1.6 years. Fifty-six percent of patients had complete ablation of Barrett glandular epithelium, with a single session of Ps-PDT. Treatment failure was detected in four patients, with persistent HGD or carcinoma that required subsequent curative esophagectomy. A combined Mayo Clinic study at two independent sites enrolled 142 patients (60 patients at Jacksonville, Florida, and 72 patients at Rochester, Minnesota) for treatment with Ps-PDT, and followed these patients for a mean of 19 months. Complete elimination of BE was noted in 50% and 35% of patients, respectively. A balloon centering device was not used during the treatment sessions. Any residual disease detected after Ps-PDT was treated with argon plasma coagulation (APC), resulting in elimination of HGD in 100% and 80% of patients, respectively. The rates of post-PDT complications and stricture formation were 20% and 27%, respectively, rates comparable to those previously reported by Overholt. There was also a transient weight loss in patients who suffered from post-PDT chest discomfort or odynophagia. The number of patients who reported experiencing cutaneous photosensitivity was similar in the Minnesota and Florida patients. The rate of residual subsquamous epithelium was 0% and 4%, respectively, and 4% (n = 5) had residual dysplasia or neoplasm, ultimately requiring curative esophagectomy. In an effort to reduce the rate of stricture formation, a group of 60 patients with BE-HGD were treated with PDT alone or PDT combined with oral prednisone, but this strategy did not impact the rate of stricture formation. In the group given PDT alone, the stricture rate was 16% compared with 29% when PDT was combined with prednisone. Updated studies have compared the results of Ps-PDT alone and combined with endoscopic mucosal resection, and in a comparative cohort study with patients who have undergone esophagectomy. These studies found a similar overall survival in patients treated with endoscopic therapy using electromagnetic radiation and PS-PDT compared with surgery. The General Infirmary at Leeds, UK and the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, reported similar efficacy in patients with BE-HGD and esophageal carcinoma. Foroulis and Thorpe retrospectively evaluated the effectiveness of Ps-PDT in 31 patients with BE-HGD, 10 patients with intramucosal carcinoma, and 6 patients with endosonography stage T2 carcinoma, during a median follow-up of 10 months. In patients with HGD or intramucosal cancer, the treatment response was 80.9%. In patients with more advanced disease (T1b/T2), 2 of the 6 patients who were unfit for surgical resection had a complete response. Keeley and colleagues reviewed their experience using Ps-PDT in 50 patients treated for BE-HGD (13 patients) or locally advanced carcinoma, with a mean follow-up of 28 months. Sixteen patients also received treatment with chemoradiation. At last follow-up, 16 patients were alive and disease free, and 15 patients were receiving additional treatment for persistent or recurrent disease. The study concluded that Ps-PDT was potentially curative for patients with BE-HGD and superficial esophageal carcinomas, but not for more advanced disease.
The Photodynamic Therapy for Barrett’s Esophagus (PHO-BAR) trial was the first multicenter randomized control trial to evaluate the utility of Ps-PDT in patients with BE-HGD to be approved by the FDA. The study involved 30 sites, used an expert centralized pathology laboratory, and studied 208 patients randomized to PDT plus omeprazole or omeprazole alone (20 mg twice daily). After the initial treatment with Ps-PDT at 12 months, 41% of patients had complete remission of BE, and 72% had complete elimination of BE-HGD. This was statistically significant compared with the group with omeprazole alone. Treatment with Ps-PDT also decreased the rate of progression to adenocarcinoma from 28% in the drug-only group, to less than 10% in the PDT-plus-omeprazole group. These results were maintained at 2 years follow-up, resulting in the approval of Ps-PDT for treatment of BE-HGD in North America, United Kingdom, mainland Europe, and Japan. Recently, Overholt and colleagues reported a 5-year follow-up of the original study. They found persistent successful elimination of BE-HGD significantly more often in patients from the Ps-PDT-plus-omeprazole group (77%), compared with 39% of patients in the omeprazole-alone group. The secondary outcome of progressing to cancer remained significantly lower (15%) in the Ps-PDT-plus-omeprazole group compared with 29% in the omeprazole-alone group. Based on these large single-center studies with long-term follow-up and the results of this randomized controlled trial, porfimer sodium has become a first-line therapy for treating BE-HGD and superficial carcinoma at many referral centers. Although Ps-PDT has been shown to be efficacious in the treatment of BE-HGD, neosquamous overgrowth of Barrett mucosa may mask persistent dysplasia or cancer (so-called buried Barrett). Bronner and colleagues analyzed the histologic specimens of 33,658 biopsies from the PHO-BAR study and found no differences in squamous overgrowth between the 2 patient groups (those treated with acid-blocker therapy only and those treated with Ps-PDT). Long term studies found no risk of missing subsquamous dysplasia or carcinoma.
Stricture formation is the most common side effect with Ps-PDT. The pathophysiology of stricture development is not known. It has been postulated that the deep burn of Ps-PDT causes an inflammatory reaction, leading to a fibrotic response, resulting in stricture formation. Yachimski and colleagues retrospectively tried to identify pretreatment variables that may lead to postablation stricture development. One-hundred and sixteen patients had a total of 160 sessions of PDT, but only 16% of patients experienced stricture after their initial treatment. Patients having a second PDT treatment had overall stricture rate of 23%. Stricture development was not related to age, gender, body mass index, or prior endoscopic mucosal resection. Independent predictors of stricture development included patients with a longer segment, multiple PDT treatments, and evidence of intramucosal carcinoma before PDT. However, there is wide variation in Ps-PDT treatment parameters; a recent study compared pretreatment evaluation protocols, PDT light dosimetry, and follow-up evaluation protocols, in 10 large PDT referral centers in the United States.
mTHPC
The chlorine derivative mTHPC is an efficient photosensitizer that has been used in Europe, mostly for the treatment of advanced head and neck cancer. A large US trial performed in patients with head and neck squamous cell carcinoma was complicated by treatment-associated tissue necrosis, tissue breakdown, and stricture formation. This highly selective photosensitizer is associated with photosensitivity that lasts for only 2 to 3 weeks after administration. In a limited number of gastroenterologic studies, mTHPC has been administered intravenously at a dosage of 0.15 mg/kg with 652 nm light activation. Gossner and colleagues have used mTHPC as salvage therapy in a small number of BE-HGD patients in whom previous treatment with ALA-PDT failed. Javaid and colleagues treated 4 patients with BE-HGD using mTHPC and an argon-pump dye laser light of 652 nm and 2 patients using a xenon arc lamp (Paterson-Whitehurst lamp, 652 nm), with equivalent results, demonstrating that efficient photosensitizers do not require high-power laser light sources for effective activation. Etienne and colleagues used mTHPC with green light PDT in 12 BE-HGD patients and 7 patients with mucosal esophageal carcinoma. There was a mean follow-up of 34 months, with only an 8% recurrence of disease. Lovat and colleagues conducted a pilot study to assess the efficacy of mTHPC, including 7 patients with BE-HGD and 12 patients with superficial esophageal cancer. Treatment results were variable, but much better for patients treated with red light, including successful ablation in 4 of 6 carcinoma patients and 3 of 4 BE-HGD patients. None of the patients treated with green light experienced successful disease eradication or reached long-term remission.
This limited experience demonstrates that although mTHPC is a potent photosensitizer, it is able to eliminate columnar epithelium in the esophagus and downgrade the degree of dysplasia, but the optimal light and drug dosimetry are unknown. Further studies are required to determine ideal treatment parameters to avoid excessive tissue necrosis and high rates of stricture.
ALA
As described earlier in this article, ALA is a prodrug that stimulates the endogenous production of PpIX, mostly within the gut mucosa. ALA and Metvix brands have been used for several years, mostly in Europe, including Scandinavia. Levulan, a commercially available form of ALA, was recently granted orphan drug status by the FDA for the treatment of patients with BE-HGD. This unusual decision comes after recent approvals for treatment of BE using Ps-PDT, radiofrequency energy ablation, and low-pressure liquid nitrogen cryotherapy ablation. Regardless, ALA has previously been used for PDT in the United Kingdom and mainland Europe for BE with dysplasia and superficial carcinoma. ALA is considered a second-generation porphyrin-type photosensitizer. It is activated using red light (635 nm) and offers several advantages, including targeting the superficial mucosal layer and a shortened photosensitivity lasting only 24 to 48 hours. The initial randomized double-blind placebo-controlled trial was conducted in the United Kingdom for patients with Barrett LGD. ALA-PDT was given orally at a dose of 30 mg/kg and activated by a green light (514 nm), to enhance superficial mucosal damage and limit the risk of stricture formation. Patients were followed for a mean of 24 months, and there was an endoscopic response in 83% of patients. After ablation, surveillance endoscopy with biopsies demonstrated that 98% of the patients were dysplasia free, with only a single case of recurrent LGD, in a 12-month follow-up. These encouraging results were also seen by other researchers treating BE-HGD. A group in Wiesbaden, Germany, has published several studies using ALA-PDT in patients with BE-HGD and superficial carcinoma; it is presumed that the authors describe studies from the same cohort of patients. Pech reported the treatment of 35 BE-HGD patients using ALA-PDT. They noted a high complete response rate in 97% of patients, at a mean follow-up of 42 months. A follow-up study examined 66 patients with BE-HGD (n = 35) or an early adenocarcinoma (n = 31). ALA was administered orally at a dose of 60 mg/kg 4 to 6 hours before endoscopy with laser light application, using light between 630 and 635 nm with an energy dose of 150 J/cm. Follow-up endoscopy procedures used argon beam coagulation or thermal potassium titanyl phosphate laser to destroy any residual glandular mucosa. An intensive endoscopic surveillance program scheduled endoscopy at 1, 2, 3, 6, 9, and 12 months, with procedures every 6 months thereafter for 5 years. During a follow-up period, with a mean of 37 months, 97% of patients with BE-HGD and 100% of early cancer patients achieved a complete response. Disease recurrence was detected in one patient with BE-HGD (89% disease-free survival), and in 10 carcinoma patients (68% disease-free survival). However, no deaths related to Barrett neoplasia were reported. From the same group, Behrens and May recently reported complete remission with the combined use of endoscopic mucosal resection, ALA-PDT, and argon beam coagulation in 44 and 49 patients, respectively. PDT using orally administered ALA has been associated with adverse effects such as significant chest pain, elevated liver enzyme tests, acute neuropathy mimicking porphyria, and sudden death, presumably related to cardiac dysrhythmia. Although considered by some to be only of minor importance, most ALA-PDT treatment occurs in the hospital setting for safety reasons and pain control.
Ortner and colleagues attempted to avoid the risks of systemic ALA administration by using the drug topically, with 15 or 60 mg/kg body weight in an 8.5% sodium bicarbonate solution in saline, using a spray catheter during endoscopy, in 7 patients with Barrett metaplasia and 7 patients with Barrett LGD. Although it was safe and effective in ablating LGD in all 7 patients, a patient with metaplasia progressed to HGD after treatment. Complete ablation of all BE was noted in only 21% of patients after the initial PDT, and in 20% after the second PDT. Therefore, topical administration of ALA was not a reliable method of ablation in these patients. Several small randomized trials have been performed using ALA-PDT in patients with Barrett metaplasia or LGD. ALA-PDT has performed poorly in studies that compared its use with another endoscopic ablation treatment. Specifically, Ragunath and colleagues studied 26 patients with Barrett dysplasia (23 with LGD, 3 with HGD) and found that the use of argon beam coagulation was more effective, less expensive, and associated with fewer complications, compared with ALA-PDT. Similar disappointing results were reported in a study in Sheffield of 68 patients with Barrett metaplasia and in a study from Adelaide, South Australia, in which 30 patients with Barrett LGD were treated with 30 mg/kg of ALA. In the Australian study, the ALA outcomes compared well with those of patients treated with APC. A trial in Rotterdam was the only positive randomized trial. The investigators used 60 mg/kg ALA for PDT in 40 Barrett patients (32 metaplasia, 8 LGD), and compared ALA to APC. While successful reversal of BE was achieved in more than 3 patients in the study, multiple courses of therapy were required, and one ALA-PDT patient died of sudden death. The authors did not recommend those treatments for “prophylactic ablation of BE.” In a study in Amsterdam published the same year, 20 patients who had BE-HGD that persisted after endoscopic mucosal resections were treated with ALA-PDT (40 mg/kg). The authors defined complete remission as the absence of BE-HGD in biopsies, taken at 2 surveillance endoscopy procedures. After ALA-PDT, all patients had persistent BE (median regression was 50%), and 5 of 20 patients (25%) had persistent HGD at surveillance examinations after PDT. Subsequent follow-up procedures found recurrence of HGD or carcinoma in another four patients, from 6 to 15 months after PDT. These findings suggest that ALA-PDT may be unreliable for treating patients with advanced disease (HGD or carcinoma). Regardless of the initial therapy used, all BE must be destroyed at follow-up endoscopy procedures to prevent the development or recurrence of carcinoma. In May 2007, an abstract from Mackenzie and colleagues presented the results of a dosimetry study of 72 patients with BE-HGD. They compared the use of red or green light with varying doses of ALA. The main treatment outcome was the development of cancer after ALA-PDT. In the patients treated using the higher doses of ALA (60 mg/kg) and higher energy red light (1000 J/cm), only 3% of patients were subsequently diagnosed with invasive carcinoma, at a follow-up of 36 months. However, in the other groups, a much higher rate of cancer development was noted (34%). These results were found in a subset of patients participating in a study of varying drug and light-energy doses, in which 14 patients (20%) progressed to cancer. In addition, there was no mention of concomitant acid-blocker therapy, which is important for the successful ablation of BE. If this is the optimal ALA, light dose, and wavelength, then perhaps it is time for a randomized controlled trial of Levulan PDT in combination with acid-blocker drugs, versus drug therapy alone, as was performed for Ps-PDT and is under way for radiofrequency ablation.
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