Photodynamic therapy for esophageal tumors

Between 1982 and 1987, 40 patients with esophageal tumors (19 adenocarcinomas, 19 squamous carcinomas, and two melanomas) in whom conventional treatments were unsuccessful were treated with photodynamic therapy (PDT) after injection with either hematoporphyrin derivative or dihematoporphyrin ether. Patients underwent endoscopy again two to three days and one month after PDT and as needed when symptoms recurred. At one month, the average minimal diameter opening of 28 assessable tumors increased from 6 to 9 mm. Of the 35 patients who could be evaluated one month after PDT, the average improvement in food intake was from a liquid to a soft diet. Average survival time (from time of first treatment) was 7.7 months (n = 17) for adenocarcinoma, 5.8 months (n = 12) for squamous cell carcinoma, and 25 months (n = 2) for melanoma. Two patients with stage I adenocarcinoma were alive with no evidence of disease at 11 and 23 months. One patient with stage I squamous cell cancer died 18 months after PDT, with recurrence of tumor above the treated area noted eight months after treatment. One patient with stage I melanoma died of a synchronous colon cancer 31 months after PDT, with no evidence of residual melanoma.     

Photodynamic therapy for esophageal cancer. Update

Although clinical studies with photodynamic therapy have been conducted for over 25 years, only recently has this technique become widely available for the treatment of esophageal cancer. Studies have demonstrated that it is as effective as Nd:YAG therapy for advanced esophageal malignancies while technically being somewhat easier to perform. Preliminary studies in early esophageal cancer also show effectiveness. In many ways, PDT is still in its infancy, and its exact role compared to other endoscopic treatments of esophageal cancer remains to be defined. It is expected that the development of new photosensitizers and light delivery systems will further expand the role of PDT in the diagnosis and management of esophageal neoplasms.     

Photodynamic therapy for treatment of malignant cutaneous lesions

Photodynamic therapy, employing either hematoporphyrin derivative or dihematoporphyrin ether as the photosensitizer and an argon-pumped tunable dye laser as the activating light source, was used to treat ten patients who had primary or recurrent basal or squamous cell carcinoma or infiltrating ductal cell carcinoma lesions metastatic to the skin. Of the 155 sites that were treated, various degrees of edema, erythema, and necrosis, sometimes accompanied by blistering, were evident in all areas within 24 to 48 hours of light treatment. While our follow-up periods are short, four patients are free of disease at eight months or more posttreatment, two patients have had recurrent and/or persistent disease within four months, and four patients died within nine months from metastatic disease or unrelated disorders. Continued investigation into the use of photodynamic therapy for treatment of malignant lesions appears warranted, based on these preliminary clinical results.     

Photodynamic therapy as palliation for esophageal cancer: experience in 215 patients

BACKGROUND: Photodynamic therapy (PDT) utilizes a photosensitizing agent, light, and oxygen to endoscopically ablate cancer cells. This review summarizes our experience with PDT for the palliation of bleeding or obstructing esophageal cancer (EC). METHODS: All patients with bleeding or obstructing EC treated with PDT from November 1996 through June 2002, were reviewed. After Photofrin II injection, nonthermal light treatment was delivered endoscopically. Dysphagia scores, duration of palliation, reinterventions, complications, and survival after treatment were reviewed. RESULTS: A total of 215 patients underwent 318 courses of PDT for bleeding (n = 15), obstruction (n = 277), bleeding and obstruction (n = 18), or other indications (n = 8). Tumor histology included 179 adenocarcinomas, 33 squamous cell carcinomas, and 3 undifferentiated. Seventy-five percent of EC were in the distal esophagus. In 85% of courses for obstruction, mean dysphagia scores improved pre- and post-PDT. The mean dysphagia-free interval was 66 days. Supplemental nutrition was discontinued after PDT in 8 of 27 patients (30%). Thirty-five patients required stent placement after PDT with a mean interval to reintervention of 58.5 days. PDT complications included perforation (2% of treatment courses), stricture (2%), Candida esophagitis (2%), pleural effusions (4%), and sunburn (6%). The procedure-related mortality rate was 1.8%, and median survival was 4.8 months. CONCLUSIONS: PDT offers effective palliation for patients with obstructing EC in 85% of treatment courses. The ideal EC patient for PDT palliation has an obstructing endoluminal cancer. Patients living more than 2 months may require reintervention to maintain palliation of malignant dysphagia, and a multimodality treatment approach is common.     

Photodynamic therapy with lasers and intense pulsed light

For many physicians, photodynamic therapy has become a routine part of using lasers and light sources to improve the outcomes of photorejuvenation therapies. Aminolevulinic acid photodynamic therapy (ALA-PDT) was first used in the treatment of actinic keratoses in the United States. It quickly became evident that PDT therapy for actinic keratoses had an additional cosmetic benefit, and clinical trials have confirmed the effectiveness of ALA-PDT in treating photorejuvenation with or without associated actinic keratoses. This article reviews the peer-reviewed literature regarding ALA-PDT in photorejuvenation and also summarizes the author's own techniques in using this new and exciting therapeutic method.     

Photodynamic therapy of C3H tumours in mice: Effect of drug/light dose fractionation and misonidazole

C3H mammary carcinomas transplanted to the feet of mice were treated with haematoporphyrin derivative (HPD) or Photofrin II(PII) and laser light at 630 nm. While fluence rates lower than 100 mW cm⁻² gave minimal hyperthermic effects, a slight but significant growth delay was observed in unsensitized tumours exposed to a fluence rate of 150 mW cm⁻² which induced tumour temperatures in the range 40–50°C. Different modes of fractionation of the light fluence and of the HPD dose were tested but were found to give poorer rather than better results than the application of a single light exposure 24 h after intraperitoneal injection of HPD. Different PII doses were applied together with different light fluences, keeping the product of the drug dose and light fluence constant. In the dose range 6.25–50 mg/kg body weight the resulting effect on tumours was constant, allowing for a slight effect of hyperthermia at the highest light fluences, and possibly a photodegradation of PII. Misonidazole given before photodynamic treatment (PDT) slightly reduced the effect of PDT on the tumour growth. When given after PDT, however, misonidazole improved the therapeutic results significantly.     

Photodynamic therapy for esophageal cancer using a 180° windowed esophageal balloon

Although delivery of uniform circumferential light is desirable during photodynamic therapy of advanced esophageal cancer in humans, early esophageal cancer may need only targeted treatment. Studies were performed in the canine esophagus of eight animals to investigate whether use of a “windowed” (shaded) centering balloon would improve targeted illumination of esophageal mucosa for photodynamic therapy. Shaded balloons were developed with a 2-cm-long, 360° or 180° clear “window.” Photofrin 4 mg/Kg was used as the photosensitizer. Light at 630 nm was delivered at 300 J/cm or 600 J/cm. Isotropic probes placed on the balloon wall allowed real-time measurement and verification of relatively uniform light doses delivered to esophageal mucosa during balloon photodynamic therapy. With the windowed balloon, targeted delivery of photodynamic therapy was possible. Using the 180° balloon, mucosa exposed to illumination was destroyed, whereas mucosa protected from light by the balloon shading was undamaged. Healing was complete and strictures did not occur. The shading of the balloon protected normal mucosa and prevents the formation of esophageal strictures. The “windowed” centering balloon provides a technology and technique that allows targeted delivery of uniform light during esophageal PDT. © 1994 Wiley-Liss, Inc.     

Photodynamic therapy induced esophageal stricture--an animal model: from mouse to pig

INTRODUCTION: A major limitation of photodynamic therapy (PDT) for Barrett's esophagus is the development of esophageal stricture. We developed an animal model of PDT-induced esophageal stricture to elucidate the mechanism of stricture development. Our studies began in a mouse but, due to its limitations, we advanced to a porcine model. MATERIALS AND METHODS: In the mouse model, 62 mice were injected with Photofrin (2-10 mg/kg) 48 h prior to photoactivation. Light energy (20-400 Joules/cm (J)) was delivered with a laser probe as a single dose, or fractionated doses (20-150 J). Animals were sacrificed when showing signs of distress or 6 to 18 weeks post-illumination. Esophagus was removed, with gross and microscopic examination performed on frozen specimens. To develop a pig model, six pigs were injected with Photofrin (2 mg/kg) 48 h prior to photoactivation. Light energy (400 J) was delivered via an endoscope using a laser probe as a single dose or repeated at 48 h. Animals were sacrificed if they could not eat soft food or lost more than 10% of their original weight according to the University of Pittsburgh Institutional Animal Care and Use Committee. RESULTS: Exposure of mice to doses of 400 J x 1, 125 J x 3, or 150 J x 3 fractions resulted in severe lung damage and death in 90% of the mice without any evidence of esophageal stricture. Lower energy levels caused minor lung damage and no change in the endothelial layer or a stricture. In pigs, exposure of 400 J as one or two fractions resulted in weight loss of 10% within 3 weeks. Endoscopy, upper GI, contrast swallow, and pathological and histological examination showed evidence of esophageal stricture at the exposed area. CONCLUSIONS: In the mouse model, pulmonary toxicity is the limiting factor following esophageal PDT exposure. In the pig model we induced esophageal stricture following PDT. This is the first animal model created to study esophageal strictures resulting from PDT.     

Photodynamic therapy for localised prostatic cancer: light penetration in the human prostate gland

We are investigating the feasibility of photodynamic therapy in the treatment of localised prostatic cancer. Of major importance in this form of treatment is the extent to which light penetrates the target organ; hence, our interest in the optical properties of the human prostate gland. We obtained three whole prostates from autopsies of patients who died of non-urological causes. Red light was launched interstitially and detector fibres measured light intensity as a function of distance from the delivery fibre end. The optical constants derived from the three prostates were almost identical and indicated that light was predominantly scattered rather than absorbed (mean absorption and scattering coefficients 0.07 +/- 0.02 mm.-1 and 0.86 +/- 0.05 mm.-1 respectively). In a comparison of the tissue penetration by four different wavelengths, 633 nm red light was found to be transmitted best. Light propagation in the heavily absorbing tissue of the human liver was 4.3 times poorer than in the prostate. Such a combination of low absorption and high scattering characteristics in prostatic tissue would enhance the effectiveness of PDT. The optical constants derived will enable "light treatment planning" in patients with prostatic cancer.     

Photodynamic therapy for rat pituitary tumor in vitro and in vivo using pheophorbide-a and white light

This is the first report on the use of photodynamic therapy (PDT) for rat pituitary tumor in vivo. Rat pituitary tumor (GH3) cells were cultured, GH3 tumor was subcutaneously implanted in nude mice, and pheophorbide-a (Ph-a) and white light were prepared. Photocytotoxicity proportional to Ph-a concentration, intensity of irradiation, and incubation time was observed in vitro. Despite the delay in the disappearance of Ph-a from the tumor, Ph-a in the pituitary gland rapidly decreased after intravenous administration in vivo. Through PDT, the tumor grossly disappeared, the plasma levels of rat growth hormone secreted from the tumor also remarkably decreased, and the development of giantism was inhibited. These results indicate that PDT is effective against rat pituitary tumor.     

Combined therapy for esophageal varices: sclerotherapy, embolization, and splenopneumopexy

A new approach consisting of sclerotherapy, embolization, and splenopneumopexy was designed to treat esophageal varices, which were caused by cirrhosis of the liver in 13 patients and by idiopathic portal hypertension in three. No serious complications occurred. Fifteen of the patients were well and without recurrent bleeding or encephalopathy during the 29-month follow-up period. One patient died of hepatic failure 4 months postoperatively. The varices either disappeared or were significantly improved. Placement of a portopulmonary shunt by splenopneumopexy is a safe, simple, and effective procedure for the resolution of varices that recur following sclerotherapy.     

Photodynamic therapy with methyl aminolevulinate for prevention of new skin lesions in transplant recipients: a randomized study

BACKGROUND: Organ transplant recipients on long-term immunosuppressive therapy are at increased risk of non-melanoma skin lesions. Repeated field photodynamic therapy using topical methyl aminolevulinate (MAL) may have potential as a preventive treatment. METHODS: This open randomized, intrapatient, comparative, multicenter study included 81 transplant recipients with 889 lesions (90% actinic keratoses (AK)]. In each patient, the study treatment was initially administered to one 50 cm area on the face, scalp, neck, trunk, or extremities (n=476 lesions) twice (1 week apart), with additional single treatments at 3, 9, and 15 months. On each occasion, the area was debrided gently and MAL cream (160 mg/g) applied for 3 hr, before illumination with noncoherent red light (630 nm, 37 J/cm2). The control, 50 cm2 area (n=413 lesions) received lesion-specific treatment (83% cryotherapy) at baseline and 3, 9, and 15 months. Additionally, all visible lesions were given lesion-specific treatment 21 and 27 months in both treatment and control areas. RESULTS: At 3 months, MAL photodynamic therapy significantly reduced the occurrence of new lesions (65 vs. 103 lesions in the control area; P=0.01), mainly AK (46% reduction; 43 vs. 80; P=0.006). This effect was not significant at 27 months (253 vs. 312; P=0.06). Hypopigmentation, as assessed by the investigator, was less evident in the treatment than control areas (16% vs. 51% of patients; P<0.001) at 27 months. CONCLUSION: Our results suggest that repeated field photodynamic therapy using topical MAL may prevent new AK in transplant recipients although further studies are needed.     

Optimal light dose for interstitial photodynamic therapy in treatment for malignant brain tumors

BACKGROUND AND OBJECTIVE:The primary goal was to determine the maximal tolerable light dose that can be administered to patients undergoing multifiber interstitial photodynamic therapy (PDT) of malignant brain tumors at a fixed dose of photosensitizer. STUDY DESIGN/MATERIALS AND METHODS: Eighteen patients (12 glioblastomas, 5 anaplastic astrocytoma, and 1 malignant ependymoma) were included in this study. The total light dose delivered to the tumor was divided into three groups of six patients each: 1,500-3,700 J, 3,700-4,400 J, and 4,400-5,900 J. RESULTS: Five patients (all glioblastomas) demonstrated postoperative permanent neurologic deficits. None of the patients in 1,500-3,700 J, two patients in 3,700-4,400 J, and three patients in 4,400-5,900 J had neurologic deficits. Glioblastomas recurred more often than anaplastic astrocytomas. Increasing the light dose did not make a difference in local/regional control of glioblastomas. Patients with anaplastic astrocytomas survived (mean, 493 days) longer than patients with glioblastomas (mean, 116.5 days) after PDT. Four patients had prolonged survival (more than a year) after PDT. CONCLUSIONS: Increasing the total light dose delivered to the tumor increases the odds of having a permanent neurologic deficit but does not increase survival or time to tumor progression. There was no difference in local or marginal recurrence with increasing light dose. Recurrent anaplastic astrocytomas tend to do better than recurrent glioblastomas with PDT.