Efficacy and safety of photodynamic therapy with temoporfin in curative treatment of recurrent carcinoma of the oral cavity and oropharynx.

Therapeutic options for recurrent carcinoma of the upper aérodigestive tract (UADT) are limited. The prognosis of these tumours remains poor with significant rate of recurrence and a lower median survival time. Photodynamic therapy (PDT) is a relatively new therapeutic alternative which combines the use of a photosensitising agent and light to induce a cytotoxic effect on the tissues. This is a retrospective single-centre study carried out in patients with a recurrence of an oral cavity or oropharyngeal carcinoma or a second appearance of tumour in a previously irradiated area. There were no metastases in lymph nodes or other organs. Laser treatment was carried out 96 h after temoporfin (Foscan(®)) injection. In our series we had 14 cases with a complete response, 1 partial response. Overall survival at 1 year was 72 % and 36 % at 5 years. Disease-specific survival at 1 year was 82 % and 45 % at 5 years. Recurrence-free survival at 1 year was 52 % and 34 % at 5 years. Side effects mainly described are pain in the area of illumination, well controlled. PDT with Foscan(®) gives useful results in terms of survival and improvement in quality of life with few adverse events or severe complications. The fact that it has low toxicity and that treatment sessions can be repeated mean it should be considered in the therapeutic armamentarium for recurrent carcinoma of the UADT.

Side-by-side comparison of photodynamic therapy and pulsed-dye laser treatment of port-wine stain birthmarks.

BACKGROUND: Pulsed-dye laser (PDL)-mediated photothermolysis is the current standard treatment for port-wine stain (PWS) birthmarks. Vascular-targeted photodynamic therapy (PDT) might be an alternative for the treatment of PWS. OBJECTIVES: To compare clinical outcomes of PDT and PDL treatment of PWS. METHODS: Two adjacent flat areas of PWS lesions were selected from each of 15 patients (two male and 13 female; age 11-36 years) and randomly assigned to either single-session PDL or PDT. PDL was delivered using a 585-nm pulsed laser. PDT was carried out with a combination of haematoporphyrin monomethyl ether (HMME) and a low-power copper vapour laser (510.6 and 578.2 nm). Clinical outcomes were evaluated colorimetrically and visually during follow-up. RESULTS: A total of nine red PWS lesions and six purple PWS lesions were treated. For red PWS, colorimetric assessment showed that the blanching rates of PDL and PDT at 2 months ranged from -11% to 24% and 22% to 55%, respectively. For purple PWS, blanching rates of PDL and PDT ranged from 8% to 33% and 30% to 45%, respectively. Overall, there was a significant difference between the blanching effect of single-session PDL treatment and a single-session PDT treatment. CONCLUSIONS: This side-by-side comparison demonstrates that PDT is at least as effective as PDL and, in some cases, superior. The true value of PDT for the treatment of PWS deserves further investigation.

Denture stomatitis treated with photodynamic therapy: five cases.

OBJECTIVE: Photodynamic therapy (PDT) is an effective method for Candida spp. inactivation in vitro and in vivo, but as yet, no clinical trial has been conducted. This report describes 5 cases of denture stomatitis (DS) treated with PDT. STUDY DESIGN: Five subjects with clinical and microbiologic diagnosis of DS were submitted to 6 sessions of PDT 3 times a week for 15 days. In each session, patients' dentures and palates were sprayed with 500 mg/L Photogem, and, after 30 minutes of incubation, irradiated by light-emitting diode light source at 455 nm (37.5 and 122 J/cm(2), respectively). Cultures of Candida spp. from dentures and palates and standard photographs of the palates were taken at baseline (day 0), at the end of the treatment (day 15), and at follow-up time intervals (days 30 and 60). RESULTS: Four patients showed clinical resolution of DS (no inflammation) after PDT sessions, and only 1 subject demonstrated reduction in palatal inflammation. Recurrence of DS was observed in 2 patients during the follow-up period. CONCLUSIONS: PDT appears to be an alternative treatment for DS.

Efficacy and safety of hemoporfin in photodynamic therapy for port-wine stain: a multicenter and open-labeled phase IIa study.

BACKGROUND/PURPOSE: This phase IIa study aimed to study the efficacy and safety of hemoporfin in photodynamic therapy (PDT) with a 532 nm continuous laser for port-wine stain (PWS). METHODS: In this 8-week open-labeled study in three centers, three different laser exposure times (532 nm continuous laser for 20, 30 and 40 min) were used in stage I, group A, stage II, group B and stage III, group C, respectively. Primary efficacy assessment was performed by an independent group of experts, who reviewed the standardized photos. Secondary efficacy assessment consisted of the subjective grading of the PWS fading by the investigators and the patients. Treatment reactions and adverse events (AE) were recorded separately. RESULTS: Forty patients were initially enrolled in the study, but stage III had to be cancelled eventually for the safety of the patients. Patients in groups A and B showed similar satisfactory results in efficacy assessments, the total 'response' rate being 80.0% and 94.7% in groups A and B, respectively. The AE rates were also similar in the two groups. Self-limiting photosensitive dermatitis and hyperpigmentation were the most frequently observed AE. CONCLUSION: Hemoporfin-PDT is effective and safe for patients with PWS aged 16-50.

Photoactivated disinfection of Streptococcus intermedius through dentin disc at clinically relevant intervals: an in vitro study.

In this present study we have tested the impact of porfimer sodium (Photofrin, AXCAN PHARMA Inc., Quebec, Canada) photoactivated disinfection (PD) on cells of Streptococcus intermedius in suspension. In order to provide basic data to support future clinical studies of PD in dentistry the study used exposure to Quartz-tungsten-halogen (QTH) dental curing light for clinically relevant time periods to activate Photofrin and measured its effectiveness under a variety of conditions including activation through dentin hard tissue. S. intermedius was grown in planktonic suspension for 48h. Nine groups were formed: three control groups (1-3) and six experimental groups (4-9). Groups 4-6 tested the use of Photofrin treatment combined with QTH light at various intervals of irradiation (5, 15 and 60s). Groups 7-9 were similar to groups 4-6 with the exception that irradiation commenced through a dentin disc. Following treatment, bacteria were plated. Colony counts were measured following 72h incubation at 37 degrees C. Statistical analysis was carried out by one-way ANOVA at a 95% confidence level. A significant reduction in S. intermedius colony counts was observed for all experimental groups and one control group. The reduction in numbers of colonies in the experimental groups varied from 79.28 to 99.40% with an average of 94.61%. Reduction in viable bacterial cells indicated a strong relationship between power density and irradiation interval. When curing light energy density was lower due to the irradiation through the 1mm dentin disc, prolonged irradiation interval enhanced bacterial kill. In conclusion, where direct irradiation is not possible for PD treatment, irradiation through dentin may still be done successfully within a clinically relevant interval.

Hematoporphyrin-based photodynamic therapy for cutaneous squamous cell carcinoma in cats.

Photodynamic therapy (PDT) using a haematoporphyrin derivative (Photogem, General Physics Institute and clustes Ltda) as photosensitizer and light emitting diodes (LEDs) as the light source was evaluated in 12 cats with cutaneous squamous cell carcinoma. Lesions were illuminated with LEDs, (300 J/cm for 30 min) 24 h after the administration of the photosensitizer. Clinical responses were classified as complete disappearance of the tumour with total re-epithelialization; partial response (a reduction greater than 50%); and no response (less than 50% reduction). Tumours localized to the pinna treated with one (n = 3) or two (n = 4) applications of PDT yielded no response. Highly invasive tumours of the nose and nasal planum also showed no response, after two treatments (n = 2). A combination of PDT and surgery was performed in three cases. Two cats showed partial response and one complete response with one application of therapy 30 days after nasal surgery. Small and noninfiltrative lesions (n = 3) of the nasal planum showed a PR with one application (n = 2) and a CR with two applications (n = 1). This study shows that PDT using Photogem and LEDs can provide local control of low-grade feline squamous cell carcinoma. The addition of PDT to surgery in more invasive cases may help prevent recurrence.

The use of photodynamic therapy for diseases of the esophagus.

This is a review of the uses, history, and current status of photodynamic therapy for diseases of the esophagus, specifically Barrett's dysplasia and early esophageal carcinoma. This paper describes the clinical experience of photodynamic therapy and compares the use of various photosensitizer drugs. Finally, important biophotonics developments are discussed, including their anticipated impact for improved endoscopic detection of dysplasia and carcinoma. In addition, methods for real-time photodynamic therapy and light dosimetry are provided in order to optimize ablation treatment outcomes while minimizing the risk of complications.

[Hematoporphyrin derivative-mediated photodynamic therapy for human nasopharyngeal carcinoma: a comparative study with CNE2 and C666-1 cell lines in vitro].

OBJECTIVE: To investigate biological effect of hematoporphyrin derivative (HpD) photodynamic therapy (PDT) on in vitro cultured nasopharyngeal carcinoma (NPC) cell lines CNE2 and C666-1. METHODS: CNE2 and C666-1 cells cultured in vitro were incubated in a medium containing HpD at different concentrations (0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, and 4.0 microg/ml) for 4 h followed by exposure to different light doses (2, 5, 10, and 20 J/cm2) using a diode laser at 630 nm with power density of 20 mW/cm2. After 24 h of incubation with HpD-PDT, the survival rate of CNE2 and C666-1 cells were analyzed by MTT assay. RESULTS: HpD-PDT produced effective killing of CNE2 and C666-1 cells cultured in vitro, and the killing effects were positively correlated with HpD concentration and the irradiation dose. Exposure of CNE2 and C666-1 cells to irradiation dose of 20 J/cm2 resulted in the IC50 of 0.7 and 1.2 microg/ml, respectively (P<0.01). With the same HpD concentration and irradiation dose, the survival rate of C666-1 cells, however, was significantly higher than that of CNE2 cells (P<0.05). CONCLUSION: HpD-PDT may result in effective killing of CNE2 and C666-1 cells cultured in vitro, although C666-1 cells are less sensitive to HpD-PDT than CNE2 cells.

Differential sensitivities of pathogens in red cell concentrates to Tri-P(4)-photoinactivation.

BACKGROUND AND OBJECTIVES: Photodynamic treatment (PDT) with the cationic porphyrin, mono-phenyl-tri-(N-methyl-4-pyridyl)-porphyrin chloride [Tri-P(4)], has previously been shown to be effective at inactivating vesicle stomatitis virus (VSV) in red cell concentrates (RCC) with limited damage to red blood cells (RBC). The aim of this study was to determine the pathogen-inactivating capacity of PDT with Tri-P(4) for a broader range of pathogens and to establish the associated effect on in vitro RBC quality. MATERIALS AND METHODS: A series of viruses and bacteria was spiked into 60% RCC. Pathogen inactivation was determined after PDT with 25 microm Tri-P(4) and red light up to 360 kJ/m2. Human immunodeficiency virus (HIV)-infected cells were evaluated for cell death induction, and RCC were analysed for the induction of haemolysis and ATP content. RESULTS: For the lipid-enveloped viruses bovine viral diarrhoea virus, HIV and pseudorabies virus, and for the Gram positive bacterium, Staphylococcus aureus, and the Gram-negative bacteria, Pseudomonas aeruginosa and Yersinia enterolitica, inactivation of > or = 5 log10 was measured after 60 min of PDT with Tri-P(4). The required treatment time to achieve this level of inactivation was four times longer than required for VSV. For cell-associated HIV, only 1.7 log10 of inactivation was found, despite clear induction of cell death of HIV-infected cells. The non-enveloped virus, canine parvovirus, was completely resistant to the treatment. PDT of RCC with Tri-P(4) for 60 min, and subsequent storage in AS-3, resulted in 4% haemolysis after 35 days of storage. The ATP content of untreated and treated RBC declined with similar kinetics during storage. CONCLUSION: PDT of RCC with Tri-P(4) for 60 min inactivates a wide range of pathogens, but not cell-associated HIV and a non-enveloped virus, and compromises RBC quality. This reduces the suitability of PDT with Tri-P(4) for red cell sterilization. Therefore, further improvements in the treatment procedures to potentiate pathogen inactivation and to preserve RBC integrity will be required to generate an effective treatment for sterilizing RCC.

[Preparation of hematoporphyrin-herceptin photoimmunoconjugate for photoimmunotherapy].

OBJECTIVE: To prepare photoimmunoconjugate of hematoporphyrin (HP) and herceptin, and study its killing and apoptosis-inducing effect on tumor cells BT-474. METHODS: HP-herceptin photoimmunoconjugate was synthesized with EDCI as the condensator. After exposure of the cells to 630 nm laser, the killing effect of the conjugate and cell apoptosis were evaluated by MTT assay and flow cytometry. RESULTS: Compared with free HP at equivalent dose, the immune reactivity, killing effect and the apoptosis-inducing effect of HP-herceptin immunoconjugate on BT-474 cells was enhanced (P<0.05). CONCLUSION: The killing effect of HP-herceptin immunoconjugate is stronger than free HP on BT-474 cells.

Synergism of epidermal growth factor receptor-targeted immunotherapy with photodynamic treatment of ovarian cancer in vivo.

BACKGROUND: Epithelial ovarian cancer often develops resistance to standard treatments, which is a major reason for the high mortality associated with the disease. We examined the efficacy of a treatment regimen that combines immunotherapy to block the activity of epidermal growth factor receptor (EGFR), overexpression of which is associated with the development of resistant ovarian cancer, and photodynamic therapy (PDT), a mechanistically distinct photochemistry-based modality that is effective against chemo- and radioresistant ovarian tumors. METHODS: We tested a combination regimen consisting of C225, a monoclonal antibody that inhibits the receptor tyrosine kinase activity of EGFR, and benzoporphyrin derivative monoacid A (BPD)-based PDT in a mouse model of human ovarian cancer. Therapeutic efficacy was evaluated in acute treatment response and survival studies that used 9-19 mice per group. Analysis of variance and Wilcoxon statistics were used to analyze the data. All statistical tests were two-sided. RESULTS: Mice treated with PDT + C225 had the lowest mean tumor burden compared with that in the no-treatment control mice (mean percent tumor burden = 9.8%, 95% confidence interval [CI] = 2.3% to 17.3%, P < .001). Mean percent tumor burden for mice treated with C225 only or PDT only was 66.6% (95% CI = 58.7% to 74.4%, P < .001) and 38.2% (95% CI = 29.3% to 47.0%, P < .001), respectively. When compared with PDT only or C225 only, PDT + C225 produced synergistic reductions in mean tumor burden (P < .001, analysis of variance) and improvements in survival (P = .0269, Wilcoxon test). Median survival was approximately threefold greater for mice in the PDT + C225 group than for mice in the no-treatment control group (80 days versus 28 days), and more mice in the PDT + C225 group were alive at 180 days (3/9; 33% [95% CI = 7% to 70%]) than mice in the C225-only (0/12; 0% [95% CI = 0% to 22%]) or PDT-only (1/10; 10% [95% CI = 0.2% to 44%]) groups. CONCLUSION: A mechanistically nonoverlapping combination modality consisting of receptor tyrosine kinase inhibition with C225 and BPD-PDT is well tolerated, effective, and synergistic in mice.

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.

Optimization of light dosimetry for photodynamic therapy of Barrett's esophagus: efficacy vs. incidence of stricture after treatment.

BACKGROUND: Photodynamic therapy (PDT) may be used to ablate high-grade dysplasia/early stage cancer (HGD/T1) in patients with Barrett's esophagus. PDT may result in esophageal stricture. This nonrandomized, unblinded, dose de-escalation study in consecutive patients was designed to determine the lowest light dose effective for ablation of HGD/T1 while reducing the incidence of stricture. METHODS: A total of 113 patients received an injection of porfimer sodium (2 mg/kg). Three days later, 630 nm light was delivered by using a 20-mm-diameter PDT balloon at doses of 115 J/cm (n=59), 105 J/cm (n=18), 95 J/cm (n=17), or 85 J/cm (n=19). Treatment efficacy was determined by obtaining biopsy specimens of the treated area 3 months later. The incidence of stricture was determined by the need for esophageal dilation to treat dysphagia. A stricture was considered severe if 6 or more dilations were required. RESULTS: The incidence of severe stricture was related to the light dose. At 115 J/cm, 15.3% of patients developed severe strictures compared with 5.3% to 5.6% of those treated with the lower doses. At a light dose of 115 J/cm, 17.0% of patients had residual HGD/T1. Light doses of 105 J/cm, 95 J/cm, and 85 J/cm resulted in residual HGD/T1 in 33.3%, 29.4%, and 31.6% of patients, respectively. None of the observations were statistically significant. CONCLUSIONS: Decreasing the light dose below 115 J/cm appeared to result in a reduced incidence rate of severe stricture but higher relative frequencies of residual HGD/T1 in Barrett's esophagus.

Photobleaching kinetics of Photofrin in vivo and in multicell tumour spheroids indicate two simultaneous bleaching mechanisms.

We present a detailed investigation of Photofrin photobleaching and photoproduct accumulation. Fisher rats were sensitized with 10 mg kg(-1) Photofrin and irradiated 24 h later with 514 nm light at 5 or 100 mW cm(-2). Fluorescence spectra were collected from the skin throughout treatment, and sensitizer bleaching and fluorescent photoproduct formation were quantified using spectral analysis. Photofrin bleaching was slightly more rapid at the higher irradiance under these conditions. However, accumulation of photoproduct was significantly enhanced at lower irradiance. To interpret these unexpected findings, we developed a new mathematical model in which reactions between singlet oxygen (1O2) and the photosensitizer and reactions between the sensitizer triplet and biological targets are both allowed to contribute to bleaching. Predictions of this model were tested in experiments performed on EMT6 spheroids sensitized with concentrations of 2.5, 10 and 30 microg mL(-1) Photofrin and subjected to PDT. Photofrin bleaching and photoproduct formation in these spheroids were measured using confocal fluorescence spectroscopy. In qualitative agreement with the mixed-mechanism model predictions, at the highest drug concentration Photofrin bleaching was more efficient via 1O2 reactions, while at the lowest concentration triplet reactions were more efficient. At all concentrations, photoproduct accumulation was greater under conditions of abundant oxygen.

Photodynamic therapy of head and neck tumors and non-tumor like disorders.

In conclusion, we would like to emphasize that photodynamic therapy can be used as a convenient and promising tool in the treatment of various malignancies in the head and neck area. It has to be stressed that PDT is still less effective in the treatment of more advanced cases of head and neck cancer. As the method of treatment which improves the quality of life, its usefulness can be considered as well as palliative treatment of non-operative cases. Although the method is not free of several side effects, such skin phototoxicity, burning, slight pain and edema in the irradiated location. All these side effects are transient and usually they disappear within 24 hours. The photodynamic treatment always results in excellent cosmetic effects without scarring or marring which are usually encountered after routine surgical operation.

Photodynamic therapy for cholangiocarcinoma.

The prognosis of perihilar cholangiocarcinoma (CC) is limited by tumor spread along the biliary tree leading to refractory obstructive cholestasis, cholangitis, and liver failure. Palliation with biliary endoprostheses yields median survival times between 4 and 6 months for nonresectable CC. Tumor ablation with photodynamic therapy (PDT) combined with biliary stenting reduces cholestasis and significantly improves median survival time to 11.5 to 16.2 months. PDT with porfimer and laser light of 630 nm provides tumoricidal tissue penetration to a depth of only 4 to 4.5 mm that does not eradicate most tumors. Time to progression lasts approximately 6 months; in other words, PDT is required twice annually. PDT costs less and enhances quality of life and survival time as compared with chemotherapy for metastatic colon cancer. These data suggest that PDT should be offered as part of the palliative treatment of CC in hepatobiliary referral centers.

[Potential and limitations of fluorescence diagnosis and photodynamic therapy. Part II: Photodynamic therapy]. / Möglichkeiten und Grenzen der Fluoreszenzdiagnostik und photodynamischen Therapie. Teil 2: Photodynamische Therapie.

In photodynamic therapy, neoplastic issue is damaged and subsequently killed by the targeted illumination of previously photosensitized cells. This review is aimed at a comprehensive, but still easily understandable, presentation of all of the aspects of these methods relevant to ENT-doctors. Initially, an explanation of the clinically relevant difficulties in the therapy of (pre-)malignant lesions of the head and neck region, a historical synopsis of the development of this method and an illustration of the biophysical basics is given. The main part of the publication, however, revolves around the description of the current status of research and a presentation of internationally approved methods. At the end, a short overview of possible future developments in this field is given.