Photodynamic therapy for Barrett's esophagus: does light still have a role?

Photodynamic therapy was the first treatment to have been shown to significantly decrease high-grade dysplasia and cancer in patients with Barrett's esophagus. However, its use has been limited, primarily because of the side effects, which include esophageal strictures, cutaneous photosensitivity, chest pain, and nausea and vomiting. The tolerability aspects of photodynamic therapy, as well as the dosimetry, though, can be improved with existing technologies to further develop this therapy into truly a widely applicable therapy. Studies have recently been done to help identify patients more likely to suffer stricture after photodynamic therapy. In addition there has been evidence to suggest that the efficacy of photodynamic therapy also can be limited by genetic abnormalities in the mucosa. By combining knowledge of tissue biology, optical properties of the tissue, and dosimetry issues with ablation, photodynamic therapy can still have a potentially bright future.

Modeling of a type II photofrin-mediated photodynamic therapy process in a heterogeneous tissue phantom.

We present a quantitative framework to model a Type II photodynamic therapy (PDT) process in the time domain in which a set of rate equations are solved to describe molecular reactions. Calculation of steady-state light distributions using a Monte Carlo method in a heterogeneous tissue phantom model demonstrates that the photon density differs significantly in a superficial tumor of only 3 mm thickness. The time dependences of the photosensitizer, oxygen and intracellular unoxidized receptor concentrations were obtained and monotonic decreases in the concentrations of the ground-state photosensitizer and receptor were observed. By defining respective decay times, we quantitatively studied the effects of photon density, drug dose and oxygen concentration on photobleaching and cytotoxicity of a photofrin-mediated PDT process. Comparison of the dependences of the receptor decay time on photon density and drug dose at different concentrations of oxygen clearly shows an oxygen threshold under which the receptor concentration remains constant or PDT exhibits no cytotoxicity. Furthermore, the dependence of the photosensitizer and receptor decay times on the drug dose and photon density suggests the possibility of PDT improvement by maximizing cytotoxicity in a tumor with optimized light and drug doses. We also discuss the utility of this model toward the understanding of clinical PDT treatment of chest wall recurrence of breast carcinoma.

[Interstitial photodynamic laser therapy for liver metastases: first results of a clinical phase I-study]. / Interstitielle Photodynamische Lasertherapie zur Behandlung von Lebermetastasen: Erste Ergebnisse einer in vivo Phase I-Studie.

PURPOSE: Development and evaluation of a new photodynamic treatment technique for the laser therapy of liver malignancies MATERIAL AND METHODS: The combination with new catheter systems enables the use of the photodynamic therapy (PDT) to treat also tumors in parenchymal organs. So far it is mainly used to treat superficial or endoluminal tumors. The presented study is part of a multicenter phase I-study. We treated 5 patients with colorectal liver metastases with the new photosensitizer SQN 400 and following interstitial photodynamic laser treatment. Evaluation of tumors were performed by contrast-enhanced CT scans. RESULTS: In the contrast enhanced CT scans the development of a complete necrosis within a radius of 1 cm around every single fibre could be shown. Additional the ablation of tumors with the combined use of several fibres is possible. Severe complications or toxicities were not observed. CONCLUSION: The photodynamic laser therapy of liver malignancies is a minimal invasive procedure with little side effects which produces sharply defined yet small volumes of necrosis.

Shape-memory alloy loop snare for endoscopic photodynamic therapy of early gastric cancer.

BACKGROUND AND STUDY AIMS: Photodynamic therapy (PDT) has proved effective in the treatment of gastric cancer, but there is room for improvement. To achieve the technical goal of carrying out endoscopic PDT, endoscopists need to determine the precise area for laser irradiation at adequate dosages. This report describes the use of a shapememory alloy (SMA) loop snare as a useful tool in endoscopic PDT. PATIENTS AND METHODS: Eleven patients with biopsy-proved early gastric cancer were treated with endoscopic PDT after intravenous injection of Photofrin II (2 mg/kg b.w.). Five patients underwent PDT using the SMA loop snare, and six underwent PDT without the use of the device. Cancer lesions smaller than 2 cm in diameter were irradiated with an excimer-dye laser (4 mJ, 80 Hz, 630 nm) for 20 min. RESULTS: All five patients (100%) treated with PDT using the SMA loop snare, and four of the six patients (67%) treated with PDT without use of the SMA loop snare, showed complete remission. CONCLUSIONS: The SMA loop snare routinely forms a circle 2 cm in diameter, covering an area of 3.14 cm2, and makes it possible to mark and calculate the precise area of cancerous lesions for irradiation at appropriate dosages. The findings of this study suggest that the SMA loop snare is an effective tool for PDT in early gastric cancer.

Photodynamic therapy of colorectal cancer using a new light source: from in vitro studies to a patient treatment.

PURPOSE: Photodynamic therapy (PDT) is a relatively new alternative modality for palliation of rectal cancer. Current source of light for PDT are laser systems that are expensive and not necessarily needed for PDT. We evaluated a new nonlaser light source for PDT, Versa-Light. METHODS AND RESULTS: In vitro PDT--CT26 murine colon carcinoma cells were incubated with aluminum phthalocyanine (AlPcS4) for 48 hours and subjected to photoradiation using Versa-Light, and viability was assessed. There was a significant decrease in viability of treated cells compared with controls. In vivo PDT--BALB/c mice were injected either subcutaneously or intrarectally with CT26 cancer cells. IP AlPcS4 (2.5 mg/kg) was injected when tumors were visible. After 24 hours, mice were subjected to photoradiation. Massive tumor necrosis in response to PDT was observed. PDT also prolonged survival of treated mice. Patient treatment--A 70-year-old woman with recurrent local rectal carcinoma received intravenous Photofrin II (2 mg/kg). After 48 and 96 hours, she was subjected to direct photoradiation. After the first light session, there was complete macroscopic disappearance of the tumor. Biopsies up to 10 weeks after the treatment showed no cancer cells in the treated area. Sixteen weeks later, a randomized biopsy from previous tumor site showed carcinoma cells. CONCLUSIONS: We believe that Versa-Light, is a good light source for PDT. It was effective in both in vitro and animal studies. It can also be safely used for clinical PDT.

Light-emitting diodes as a light source for intraoperative photodynamic therapy.

The development of more cost-effective light sources for photodynamic therapy of brain tumors would be of benefit for both research and clinical applications. In this study, the use of light-emitting diode arrays for photodynamic therapy of brain tumors with Photofrin porfimer sodium was investigated. An inflatable balloon device with a light-emitting diode (LED) tip was constructed. These LEDs are based on the new semiconductor aluminum gallium arsenide. They can emit broad-spectrum red light at high power levels with a peak wavelength of 677 nm and a bandwidth of 25 nm. The balloon was inflated with 0.1% intralipid, which served as a light-scattering medium. Measurements of light flux at several points showed a high degree of light dispersion. The spectral emission of this probe was then compared with the absorption spectrum of Photofrin. This analysis showed that the light absorbed by Photofrin with the use of the LED source was 27.5% of that absorbed with the use of the monochromatic 630-nm light. Thus, to achieve an energy light dose equivalent to that of a laser light source, the LED light output must be increased by a factor of 3.63. This need for additional energy is the difference between a 630- and 677-nm absorption of Photofrin. Using the LED probe and the laser balloon adapter, a comparison of brain stem toxicity in canines was conducted. LED and laser light showed the same signs of toxicity at equivalent light energy and Photofrin doses. The maximal tolerated dose of Photofrin was 1.6 mg/kg, using 100 J/cm2 of light energy administered by laser or LED. This study concludes that LEDs are a suitable light source for photodynamic therapy of brain tumors with Photofrin. In addition, LEDs have the potential to be highly efficient light sources for second-generation photosensitizers with absorption wavelengths closer to the LED peak emission.

Cooperative clinical trial of photodynamic therapy with photofrin II and excimer dye laser for early gastric cancer.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) is a recently developed endoscopic method for treating malignant tumors. For obtaining more photodynamic action with less thermal effect, we employed as the excitation light source for PDT an excimer dye laser, which is a pulsed laser with extremely high peak power, instead of an argon dye laser, which is a continuous wave laser and has been used conventionally. STUDY DESIGN/MATERIALS AND METHODS: The effect of PDT using Photofrin II and the excimer dye laser was evaluated in 27 patients with early gastric cancer. RESULTS: Complete responses (CR) were obtained in 88% of 24 assessable patients and the response rate was 100%. CR was observed in all cases of lesions of superficial depressed type without ulceration and/or with tumor diameter less than 2 cm. Regarding toxicity, mild cutaneous reaction and photosensitivity were seen and lasted several weeks. There were no serious abnormalities in laboratory tests. CONCLUSION: We conclude that PDT is a promising modality for early gastric cancer.

Application of photodynamic therapy to the treatment of atherosclerotic plaques.

Photodynamic therapy is a therapeutic modality long studies for its application to the treatment of malignant neoplasms. Recently, studies have suggested its potential use in the treatment of atherosclerosis. In this study, two atherosclerotic plaques were induced in the abdominal aortas of 35 rabbits. The animals then received Photofrin II (Quadralogic Technologies Inc., Pearl River, NY), a photosensitizer, at doses of 5 mg/kg and 2.5 mg/kg. After 48 hours, the plaques were irradiated by a fiberoptic connected to an argon ion laser. Fluency rates from 32 mW to 256 mW and energy doses from 1.6 to 60 joules were applied. Only one of the paired plaques was irradiated, the other remaining as a control. Four weeks after treatment, the vessels were assessed. Of 26 plaques treated with photodynamic therapy, 22 were no longer grossly visible, while the nine animals that received light irradiation but no Photofrin II all had visible plaque (P < 0.001). Studies of the vessel sections confirmed a reduction in intimal thickness from 0.74 +/- 0.15 mm in matched controls as compared with 0.51 +/- 0.13 mm in animals with treated plaques. There was a concomitant enlargement of the luminal diameter from 1.13 +/- 0.51 to 1.41 +/- 0.72. On the microscopic level, plaque reduction was most complete in the groups treated with 40 and 60 joules. Different fluency rates and drug dosages did not lead to differing outcomes. Our findings indicate that photodynamic therapy with dihematoporphyrin ether met our goal of reducing plaque size and may represent a means of treating atherosclerotic plaques.

Photodynamic therapy for intracranial neoplasms: investigations of photosensitizer uptake and distribution using indium-111 Photofrin-II single photon emission computed tomography scans in humans with intracranial neoplasms.

Photodynamic therapy is being investigated as an adjuvant treatment for intracranial neoplasms. The efficacy of this therapy is based on the uptake of photosensitizer by neoplastic tissue, its clearance from surrounding brain tissue, and the timing and placement of photoactivating sources. Photofrin-II is the photosensitizer most actively being investigated. We labeled Photofrin-II with Indium-111 and studied the uptake and distribution of this agent in 20 patients with intracranial neoplasms, using single photon emission computed tomography (SPECT) with volume rendering in three dimensions. Of these patients, 16 had malignant glial tumors, 2 had metastatic deposits, 1 had a chordoma, and 1 had a meningioma. Anatomical-spatial data correlated well between the SPECT images and contrast-enhanced computed tomography or magnetic resonance images. Regions of focal uptake on SPECT images correlated with the surgical histopathological findings of the neoplasm. The kinetics of photosensitizer uptake varied according to the tumor's histological findings, the patient's use of steroids, and among patients with similar types of tumor histology. Peak ratios of target-to-nontarget tissue varied from 24 to 72 hours after injection. The study data show that, to be most effective, photodynamic therapy may need to be tailored for each patient by correlating SPECT images with anatomical data produced by computed tomography or magnetic resonance images. Photoactivating sources then can be placed, using computer-assisted stereotactics, to activate a prescribed volume of photosensitized tumor at the optimal time for treatment.

[Photodynamic therapy by coloring laser. Can it represent a therapeutic alternative for small epidermoid cancers of the esophagus?]. / La photothérapie dynamique par laser à colorant. Peut-elle représenter une alternative thérapeutique pour les petits cancers épidermoïdes de l'oesophage?

Our aim was to assess the efficacy of photodynamic therapy in inoperable patients with small esophageal carcinoma. Eleven patients were treated for squamous cell carcinomas ranging in size from 1 to 3 cm2. Hematoporphyrin (between 3 and 5 mg/kg) was injected intravenously and then the tumor irradiated at endoscopy 72 hours later with a dye laser (630 nm) at an energy of 250 joules/cm2. Complete destruction of the lesion was obtained in 6 cases with negative biopsies at 1 month. In all 6 patients, no recurrence was seen after a median follow-up of 4 months (range: 2-38). Partial destruction of the tumor was obtained in 4 cases while treatment was a complete failure in the last patient. Two instances of mild cutaneous photosensitization occurred. Two patients treated for recurrence after radiotherapy, died of esophageal perforation directly related to the procedure. Photodynamic therapy appears to be a possible effective treatment for esophageal squamous cell carcinoma in inoperable patients when other curative treatment modalities are not possible.

A light-diffusing device for intraoperative photodynamic therapy in the peritoneal or pleural cavity.

Light delivery to anatomic areas involved by tumor is critical for effective photodynamic therapy. The authors provide a detailed overview of a light-diffusing device which they have used for intraoperative illumination of the peritoneal and pleural cavities in patients with tumors involving the surfaces of these cavities. Their device represents an inexpensive modification of widely available endotracheal tubes. It has been used to deliver intraoperative photodynamic therapy in over 50 patients without episodes of device failure. When combined with a lipid-based, light-diffusing medium and on-line power/energy density monitoring, it allows homogeneous illumination of these complex surfaces.

[Use of photodynamic therapy in the treatment of refractory carcinoma in situ]. / Die Anwendung der photodynamischen Therapie zur Behandlung des therapieresistenten Carcinoma in situ.

Photodynamic therapy (PDT) is a new and innovative approach to the treatment of malignant disease. This treatment modality involves administration of a photosensitizer, which is retained in malignant tissue, followed by exposure of that tissue to light corresponding to one of the absorption bands of the drug, with resultant cell death. Several photosensitizers are currently under study, but haematoporphyrin derivative (HPD) is the drug that has been used almost exclusively in clinical urological trials. Both direct and indirect methods have been used to document the preferential concentration or retention of HPD in malignant urothelium. Although this drug is not a perfect tumour localization aid, it is perhaps the best that has thus far been studied for transitional cell carcinoma of the bladder. Over the past decade of investigation, PDT has become established to the point that it is now being tested in phase II and III trials against standard and approved drugs for the treatment of noninvasive transitional cell carcinoma of the bladder.

Treatment of the transplantable FANFT induced bladder tumors with the purpurin SnET2 and red light emitted by a pulsed frequency doubled Nd:YAG laser.

Photodynamic therapy of transplantable N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide-induced tumors engrafted onto Fischer CDF (F-344)/CrlBR rats that had been sensitized with the photosensitizer tin (ll) etiopurpurin dichloride was performed in combination with visible light (approximately equal to 660 nm) emitted by either a continuous wave argon-dye laser or a pulsed, frequency-doubled Nd:Yag laser. Tumor control was assessed either by tumor dry-weight 12 days after treatment or by the palpatory absence of tumor at 60 days after treatment. Both laser sources were effective in creating the desired photodynamic effect. This study demonstrates the potential for the use of a solid-state pulsed laser for photodynamic therapy when used in combination with the tumor sensitizer tin (ll) etiopurpurin dichloride.

A fast test system for the effect of in-vitro parameters on the sensitizing efficiency in photodynamic laser (tumor) therapy.

An optimized application of the photodynamic laser therapy for cancer treatment requires the knowledge of the effect of in-vitro parameters, such as biochemical targets and irradiation protocols, on the sensitizing efficiency. Sensitizers such as hematoporphyrin-derivatives react mainly via singlet oxygen formation with proteins and lipids within the cells when activated by light having the appropriate wave length. Single oxygen and oxygen radical formation can be determined by oxygen consumption of the reactants. An existing oxygen consumption measurement system was adapted for fast determination of the reactivity of the different parameters. Two examples of the applicability of the fast screening test system are presented here: Variation of the sensitizer to target ratio and the light intensity.

[Photodynamic therapy of bronchial cancer]. / Photodynamische Therapie des Bronchialkarzinoms.

Photodynamic therapy (PDT) with porphyrin derivatives (haematoporphyrin and dihaematoporphyrin äther/ester) and laser light of the wavelength 640 nm, is a new procedure for the treatment of carcinomas. This form of therapy is selective, can be applied through the bronchoscope, and is aimed at accomplishing curative elimination of central tumours of the lung. To date, we have successfully applied PDT in four selected patients. Our first patient was treated in April, 1987. The irradiation modalities and the clinical course are described.