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.

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.

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.

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.

Localization and photosensitization of murine tumors in vivo and in vitro by a chlorin-porphyrin ester.

Preparation of the tumor-localizing preparation called hematoporphyrin derivative involves a two-step reaction wherein hematoporphyrin is acetylated and the reaction product subjected to alkaline hydrolysis. We have proposed that the tumor-localizing fraction of this product is composed of hematoporphyrin units joined by ester linkages. Using an analogous synthetic procedure, we prepared some new sensitizers in which hematoporphyrin is esterified to chlorins (reduced porphyrins). Because of the differences in absorption spectra, the porphyrin-chlorin esters are 5-fold more potent photosensitizers than are the porphyrin-porphyrin esters, with light of wavelength greater than 600 nm.

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.

Photodynamic therapy of photofrin II and excimer dye laser on experimental tumors.

Photodynamic therapy (PDT) by combination of photofrin II and excimer dye laser was evaluated for its usefulness in experimental tumors. High antitumor effects of PDT on sarcoma 180 solid type were obtained when PDT was performed with laser irradiation at an energy of 50 or 100 J/cm2 (40 or 80 Hz, 4 mJ/pulse) 48 h after i.v. administration of photofrin II at a dose of 25 mg/kg. Under the same conditions, the antitumor effects of PDT on murine Lewis lung carcinoma, human fibrosarcoma HT-1080 and human bladder transitional cell carcinoma KK-47 were also observed. These results suggest that clinical application of PDT with photofrin II and excimer dye laser might be useful.

Comparative study of the therapeutic effect of photoactivated hematoporphyrin derivative and aluminum disulfonated phthalocyanines on tumor bearing mice.

Although the hematoporphyrin derivative (Hpd) is one of the most studied photosensitisers for photodynamic therapy (PDT), it is far from ideal. Therefore, many laboratories have been investigating a new group of sensitisers, the phthalocyanines. Particularly, in our laboratory we decided to study the aluminum disulfonated phthalocyanines (AlS2PC). They are chemically stable, readily soluble in water and have a strong absorption in the red part of the spectrum at 675 nm. Mice bearing the MS-2 fibrosarcoma treated with 5 mg/kg of AlS2PC survived indefinitely also using a low laser power of 100 mW/cm2 X 10' of exposure time, in contrast to experiments carried out with Hpd where the optical therapeutic laser power was 400 mW/cm2 X 10' and the dose of Hpd was 25 mg/kg. Furthermore, treatment of mice bearing the highly metastatic tumor, B16 melanoma, with 5 mg/kg of AlS2PC and laser light (100 mW/cm2 X 10'), significantly prolonged the survival time in respect to mice treated with 25 mg/kg of Hpd and laser light (400 mW/cm2 X 10').

Potentiation of photodynamic therapy with haematoporphyrin derivatives by glucocorticoids.

The effect of glucocorticoids on tumour destruction by photodynamic therapy (PDT) with haematoporphyrin derivative (HPD) and light has been examined in a transplantable mouse tumour model. Administration of glucocorticoid after irradiation enhanced the effect of PDT on both Lewis lung carcinoma and B16 melanoma. Administration of methylprednisolone acetate in depot form concurrently with HPD inhibited the response to PDT while soluble hydrocortisone sodium succinate had no effect. Correctly timed administration of glucocorticoid may have a place in treatment of human tumours by PDT with HPD. Glucocorticoid did not reduce the temporary photosensitivity of the skin induced by HPD.

The response of a rodent fibrosarcoma to superficial/interstitial photochemotherapy, chemotherapy or radiotherapy.

Growth and dose-response curves were established for a subcutaneously implanted isogenic fibrosarcoma in BD9 rats after treatment with photochemotherapy (PCT), using Photofrin II or polyhaematoporphyrin with superficial or interstitial 630 nm light, cyclophosphamide or gamma-irradiation. Tumour response to PCT increased with dose up to 200 J.cm-2 for superficial light or 200 J for interstitial light but no further response occurred after higher light doses. The maximum response after interstitial treatment was significantly greater than after superficial treatment where only a small margin of normal tissue was treated. The incidence of necrosis in the overlying skin was significantly less after interstitial than superficial light suggesting a better therapeutic ratio after interstitial than superficial PCT. Tumour response increased with the diameter of the treatment field after superficial light supporting the possibility of a tumour bed effect associated with PCT. The largest tumour that could be effectively treated with a single optical fibre was 12 mm. The dose-response curves for interstitial PCT and cyclophosphamide were similar but ionizing irradiation produced increasing tumour response throughout the range of doses used (5 to 30 Gy) and the maximum response was greater after radiotherapy than after PCT or chemotherapy suggesting that in this tumour model interstitial PCT is as effective as cyclophosphamide but less effective than radiotherapy.

Photodynamic therapy for early stage squamous cell carcinoma of the lung.

OBJECTIVE: To study the effectiveness of photodynamic therapy (PDT) as a therapeutic strategy in roentgenographically occult squamous cell carcinoma of the lung. MATERIAL AND METHODS: A carefully selected group of 21 patients (with 23 cancers) who had early stage squamous cell carcinoma of the lung and were eligible for surgical treatment were offered PDT as an alternative to resection. Patients underwent close follow-up with bronchoscopic surveillance and were offered resection if cancer persisted after no more than two sessions of PDT. RESULTS: A complete response was identified in 15 patients (16 cancers) after an initial PDT session. A complete response that lasted longer than 12 months was noted in 11 patients (52%). After PDT, the minimal follow-up period was 24 months. A subsequent primary lung cancer developed in 5 of the 21 patients (24%). Ten patients ultimately had surgical treatment, in 3 (30%) of whom N1 disease was identified at the time of resection. Two patients refused a surgical procedure and received alternative therapy. Therefore, nine patients (43%) were spared an operation (95% confidence interval, 21.8 to 66.6%). The mean duration of follow-up for these nine patients was 68 months (range, 24 to 116). CONCLUSION: On the basis of this investigation, we can conclude with 95% confidence that at least 22% of patients with early stage squamous cell lung cancer who are candidates for PDT can be spared surgical resection.

Bronchoscopic phototherapy with hematoporphyrin derivative for treatment of localized bronchogenic carcinoma: a 5-year experience.

Between December 1980 and April 1986 at our institution, 38 patients with cancer that involved the tracheobronchial tree (a total of 40 carcinomas) completed at least one course of hematoporphyrin derivative phototherapy. A complete response occurred in 13 patients (with 14 carcinomas). Eleven of these carcinomas did not recur during follow-up periods that ranged from 3 to 53 months. Three carcinomas recurred at 9, 12, and 35 months, respectively. For 26 carcinomas, the response was less than complete, and alternative therapy was necessary. The carcinomas in patients with a complete response were radiographically occult, were less than 3 cm2 in surface area, and appeared superficial at bronchoscopy. Our experience supports the use of hematoporphyrin derivative phototherapy as an alternative to surgical resection in carefully selected patients.

Technique of photodynamic therapy for disseminated intraperitoneal malignant neoplasms. Phase I study.

Patients with disseminated intraperitoneal malignant neoplasms were given intra-abdominal photodynamic therapy. Patients received dihematoporphyrin ethers intravenously 48 to 72 hours before laparotomy at doses of 1.5 to 3.0 mg/kg. At operation, as much tumor as possible was resected. Red light (630 nm) was delivered to all peritoneal surfaces from an argon-pumped dye laser at doses ranging from 0.2 to 3.0 J/cm2 in an escalating fashion. Viscera and peritoneal surfaces were anatomically isolated and exposed to light for intervals calculated to deliver the prescribed energy. Light was delivered to mesentery and bowel by a flat-cut optical fiber, while other areas, including diaphragm, viscera, omental bursa, gutters, and pelvis, were delivered light through a diffusing wand. Twenty-three patients (13 with ovarian cancer, eight with sarcoma, and two with pseudomyxoma peritoneii) underwent photodynamic therapy. Five of eight patients cleared positive peritoneal cytologies after treatment. Six patients remained clinically free of disease for up to 18 months, and five patients had treatment-related complications. Intraperitoneal phototherapy is technically feasible and deserving of clinical evaluation.

Selective uptake of hematoporphyrin derivative into human cerebral glioma.

The uptake of hematoporphyrin derivative (HpD) into human cerebral glioma was measured using a porphyrin extraction technique. Patients with cerebral glioma were injected with HpD at a dose of 5 mg/kg body weight 24 hours before surgery and photoradiation therapy (PRT). Biopsies of tumor, and where possible, adjacent brain and normal brain were taken for analysis of HpD uptake. HpD was selectively localized into all grades of glioma, and there was a direct correlation between the grade of glioma and HpD level in the tumor. The levels were highest in glioblastoma multiforme (mean uptake of 5.9 micrograms of HpD/g of tumor wet weight) and lower in the intermediate-grade anaplastic astrocytoma (mean uptake of 2.4 micrograms/g of tumor) and the low-grade astrocytoma (1.6 micrograms/g of tumor). Uptake into normal brain tissue taken from HpD-sensitized patients was 0.2 microgram/g. HpD was also localized into the "brain adjacent to tumor" region. The selective uptake into the low-grade glioma suggests that PRT may be of use as an adjuvant therapy in these tumors and the detection of HpD in this region indicates that PRT may control the spread of tumor infiltrating into the adjacent normal brain.

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.

Efficacy of DHE photodynamic therapy for respiratory papillomatosis: immediate and long-term results.

OBJECTIVES/HYPOTHESIS: Recurrent respiratory papillomatosis is a potentially life-threatening disease that affects both children and adults and can result in complete respiratory obstruction. Conventional therapies cannot prevent multiple recurrences. The authors have been evaluating photodynamic therapy (PDT) to treat this disease since 1988. This study compared the efficacy of PDT with dihematoporphyrinether (DHE) with traditional therapy. STUDY DESIGN: This was a randomized prospective trial of DHE-PDT. Patients were randomly assigned to receive one of two doses of DHE--3.25 mg/kg or 4.25 mg/kg body weight. They were compared with a concurrent control group. Disease extent was evaluated by direct laryngoscopy before treatment and over a 1-year period following treatment. Results were also compared with two historical cohorts of patients treated with lower doses of DHE. METHODS: Eighty-one patients, ages 4 to 74 years, with moderate to severe recurrent disease were enrolled. Forty-eight received PDT and 33 in the control group were treated with conventional therapy. Both PDT groups received 50 J laser light to activate the drug. Patients received an intravenous infusion of DHE as outpatients 48 to 72 hours before treatment. During direct laryngoscopy, light (630 nm) was delivered by an argon-pumped dye laser. Tissue biopsies were analyzed for presence of human papillomavirus (HPV). RESULTS: There was notable improvement with either drug dose over the first year. Those receiving 4.25 mg/kg DHE experienced a significantly larger decrease in papilloma growth rate. Three-year follow-up of a subset of patients confirmed that improvement was maintained. There was no impact of DHE-PDT on persistence of HPV DNA. CONCLUSION: This therapy holds promise for the treatment of laryngeal papillomas.

Pharmacokinetics of Photogem using fluorescence monitoring in Wistar rats.

In this study we investigated the pharmacokinetics of a hematoporphyrin derivative (Photogem) in Wistar rats using the fluorescence spectroscopy to evaluate the drug distribution in liver, kidney and skin tissues. The detection system is composed of a 532 nm exciting laser, a Y-type catheter for light delivery and collection, a monochromator and a computer for data acquisition. The analysis of the fluorescence spectra was based on the intensity of porphyrin emission bands from specific tissues of the investigated organ. A simple transport model is proposed to determine the accumulation and elimination times for each type of investigated tissue. The obtained results show the viability of the fluorescence spectroscopic technique for the drug concentration monitoring in different target tissues and related pharmacokinetics. These effects should be considered before any in vivo study of Photodynamic Therapy using Photogem.

Longer term assessment of photodynamic therapy for intimal hyperplasia: a pilot study.

PURPOSE: To determine the potential long term (three or six months) effectiveness of photodynamic therapy (PDT) in reducing intimal hyperplasia in swine. METHODS: Intimal hyperplasia in the abdominal aortae of swine was created by a combination of fat-supplemented diet and balloon catheter injury prior to PDT. Swine were randomly allocated into one of three groups which received either: (i) both drug and light (PDT), (ii) drug only, or (iii) light only. Twenty-four hours following administration of the photosensitizer PHOTOFRIN (porfimer sodium) at 2.5 mg/kg, two distinct 1 cm spots on the posterior wall of the abdominal aorta were illuminated by an argon pumped dye laser tuned to 630 nm for an energy fluence of 120 J/cm2. After three or six months, swine were sacrificed, perfusion fixed, and had their aortae removed for light and electron microscopy. RESULTS: Intimal hyperplasia reduction following PDT persisted for the three or six months follow up period. Experimental vessels receiving PDT showed a 26.0+/-4.5% ( n = 2, ie. four spots) and 30.8+/-5.4% ( n = 1, ie. two spots) smaller percent intimal area after three or six months of recovery, respectively. Control groups receiving either light or drug only showed less than a 6% difference in percent intimal area. Medial and adventitial layers were unaffected in all groups. Electron microscopy demonstrated that the endothelium or endothelial-like cells had regenerated in both the posterior and adjacent areas of the abdominal aortae with no clear difference between them. CONCLUSIONS: These findings suggest that PDT may be beneficial in reducing intimal hyperplasia for up to three or six months in swine.