Photodynamic therapy: occupational hazards and preventative recommendations for clinical administration by healthcare providers.

OBJECTIVE: Photodynamic therapy (PDT) as a medical treatment for cancers is an increasing practice in clinical settings, as new photosensitizing chemicals and light source technologies are developed and applied. PDT involves dosing patients with photosensitizing drugs, and then exposing them to light using a directed energy device in order to manifest a therapeutic effect. Healthcare professionals providing PDT should be aware of potential occupational health and safety hazards posed by these treatment devices and photosensitizing agents administered to patients. MATERIALS AND METHODS: Here we outline and identify pertinent health and safety considerations to be taken by healthcare staff during PDT procedures. RESULTS: Physical hazards (for example, non-ionizing radiation generated by the light-emitting device, with potential for skin and eye exposure) and chemical hazards (including the photosensitizing agents administered to patients that have the potential for exposure via skin, subcutaneous, ingestion, or inhalation routes) must be considered for safe use of PDT by the healthcare professional. CONCLUSIONS: Engineering, administrative, and personal protective equipment controls are recommendations for the safe use and handling of PDT agents and light-emitting technologies.

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 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.

The attenuation effect of 3,4-dihydroxy-phenyl lactic acid and salvianolic acid B on venular thrombosis induced in rat mesentery by photochemical reaction.

3,4-dihydroxy-phenyl lactic acid (DLA) and salvianolic acid B (SAB) are two major water-soluble components of Salvia miltiorrhiza (SM). Previous works have revealed the ability of DLA and SAB to scavenge oxygen free radicals, inhibiting the expression of adhesion molecules CD11b/CD18 in neutrophil. Cardiotonic pills (CP), which is a traditional Chinese medicine compound preparation containing DLA and SAB, was found to inhibit venular thrombosis induced by photochemical reaction (PR) in rat mesentery. The present study addressed the effect of DLA and SAB on PR-induced thrombosis in rat mesentery by utilizing a microcirculation dynamic viewing system. The result demonstrated that both DLA and SAB delayed thrombus-initiation time, while DLA also prolonged thrombus half-size time. The experiments explored the mechanism underlying that the dihydrorhodamine 123 (DHR) fluorescence in the mesenteric venular walls after PR challenge was diminished by pretreatment with either DLA or SAB, the expression of CD18 in neutrophils elicited by PR was depressed by administration of DLA, while mast cell degranulation in rat mesentery induced by PR was damped by SAB. The antioxidant potential of the two substances is likely to be responsible for their most beneficial effects on thrombosis, through either directly scavenging the peroxides produced and/or indirectly depressing the expression of adhesion molecules in neutrophil.

Influence of heating on the activity of xanthine oxidase in tumor cells subjected to the phototoxic action of hematoporphyrin derivative.

The aim of this study was to clarify the mechanism of the stimulatory effect of heat stress on generation of superoxide radical (O2-*) in tumors subjected to photodynamic therapy (PDT) with hematoporphyrin derivative (HPD). For this purpose, the effect of heating on the activity of xanthine oxidase (XOD) in tumor cells upon their photosensitization with HPD was examined; this enzyme is participated in purine catabolism and has the ability to generate O2-*, a precursor of H2O2 and very cytotoxic hydroxyl radical. The study was carried out on Ehrlich ascites carcinoma (EAC) cells, which were loaded with HPD in a serum-free medium and then irradiated with red light (lambda max = 630 nm) at 3 different temperatures (30, 37 and 44 degrees C). In the cells, the activity of XOD was assayed fluorometrically, using pterine as the substrate, whereas the production of O2-* by the nitro blue tetrazolium method. It was found that increasing of the temperature from 30 to 44 degrees C strongly (by approximately 2.5-fold) enhanced the generation of O2-* in EAC cells that correlated well with an increase in the rate of their photosensitized killing. Experiments showed that the intensification of O2-* formation could be mediated by the stimulatory effects of heating on the activity of XOD; namely, the 12 min treatment of EAC cells by HPD-PDT at a control (30 degrees C) temperature caused an about 2-fold growth in the activity of XOD, whereas the same light exposure at 44 degrees C led already to a 2.7-fold increase in the activity of this enzyme. However, incubation of EAC cells in the dark even at a hyperthermic (44 degrees C) temperature had no effect on their XOD activity. Thus, our findings strongly suggest that upon PDT with HPD the mild hyperthermia (approximately 44 degrees C) produced by photoirradiation might enhance the PDT-induced oxidative stress and, as a result, its tumoricidal effect via a rise in the activity of XOD. Besides, the obtained results suggest that severe hyperthermia (> 45 degrees C) could induce, contrary to mild hyperthermia, a reduction in the efficiency of HPD-PDT; we found that in EAC cells the raising temperature of an environment from 30 to 44 degrees C induced more than 2-fold increase in the activity of XOD, whereas further heating from 44 to 60 degrees C led to inactivation of this enzyme.

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.

Influence of temperature on the efficiency of photodestruction of Ehrlich ascites carcinoma cells sensitized by hematoporphyrin derivative.

AIM: To elucidate the mechanism of the potentiating influence of heating associated with photoirradiation on the antitumor efficiency of photodynamic therapy (PDT) with hematoporphyrin derivative (HPD). METHODS: The study was carried out on Ehrlich ascites carcinoma (EAC) cells, which were loaded with HPD in a serum-free medium and then irradiated with red light (lambda max=630 nm) at various temperatures. Cytotoxicity was estimated by the trypan blue exclusion assay. RESULTS: Our data support the view that in PDT the hyperthermia (around 44 degrees C) produced by irradiation can enhance synergistically the HPD-photoinduced tumor eradication; it was found that raising the irradiation temperature from 30 to 44 degrees C caused a substantial (approximately 1.5 fold) increase in the rate of HPD-photosensitized inactivation of EAC cells, while hyperthermia (44 degrees C) itself showed little toxic effects towards the cells. CONCLUSION: Studies indicated that the potentiating effect of heating on the antitumor efficiency of HPD-PDT could be largely explained by the stimulation of reactive oxygen species formation such as H2O2, superoxide and hydroxyl radicals. It was also found that photosensitization of EAC cells by HPD caused a strong fall in the activity of catalase (CAT) and glutathione (GSH) peroxidase, and that heating sensitized the H2O2-detoxifying enzymes to HPD-photoinduced inactivation. Under HPD-PDT, these events could result in loss of protection against accumulating H2O2; we revealed that cell-bound CAT and the GSH redox cycle play an important role in the protection of EAC cells against HPD-PDT. Moreover, our findings suggest that during PDT with HPD, an increase in the temperature of tumors could enhance the efficiency of this therapy via the stimulation of a chlorin-type photoproduct formation.

Photodynamic therapy: mechanism of action and ways to improve the efficiency of treatment.

Photodynamic therapy is treatment modality involving the administration of photosensitizing compound, which selectively accumulates in the hyperproliferative target cells followed by local irradiation with visible light of lesion. Eventually target tissue will be damaged by necrosis and apoptosis. Action of treatment is described from absorption of light till damage of tissue. Several rationale proposals to increase the efficiency of described treatment modality are suggested: to evaluate the antiproliferative activity of new coming photosensitizers, to combine photosensitization with other treatment modalities in molecular level, exploring mechanism of apoptosis, to increase the efficiency of treatment by combination with ionizing radiation, hyperthermia or ligation of peripheral benzodiazepine receptors.

Preliminary report of photodynamic therapy for intraperitoneal sarcomatosis.

INTRODUCTION: Sarcomatosis is the disseminated intraperitoneal spread of sarcoma. It is a condition for which there is no effective treatment. Photodynamic therapy (PDT) is a cancer treatment modality that uses a photosensitizing agent and laser light to kill cells. We report our preliminary Phase II clinical trial experience using PDT for the treatment of intraperitoneal sarcomatosis. METHODS: From May 1997 to December 1998 eleven patients received twelve PDT treatments for intraperitoneal sarcomatosis. Photofrin (PF) 2.5 mg/kg was administered intravenously 48 hours before surgical debulking to a maximum residual tumor size of less than 5 mm. Light therapy was administered at a fluence of 2.5 J/cm2 of 532 nm green light to the mesentery and serosa of the small bowel and colon; 5 J/cm2 of 630 nm red light to the stomach and duodenum; 7.5 J/cm2 of red light to the surface of the liver, spleen, and diaphragms; and 10 J/cm2 of red light to the retroperitoneal gutters and pelvis. Light fluence was measured with an on-line light dosimetry system. Response to treatment was evaluated by abdominal CT scan at 3 and 6 months, diagnostic laparoscopy at 3 to 6 months, and clinical examination every 3 months. RESULTS: Adequate tumor debulking required an omentectomy in eight patients (73%), small bowel resection in seven patients (64%), colon resection in four patients (36%), splenectomy in one patient (9%), and a left spermatic cord resection in one patient. Five patients (45%) have no evidence of disease at follow-up (range, 1.7-17.3 months), including patients at 13.8 and 17.3 months examined by CT. Two patients (18%) died from disease progression. Four patients (36%) are alive with disease progression. Toxicities related to PDT included substantial postoperative fluid shifts with volume overload, transient thrombocytopenia, and elevated liver function tests. One patient suffered a postoperative pulmonary embolism complicated by adult respiratory distress syndrome (ARDS). CONCLUSIONS: Debulking surgery with intraperitoneal PDT for sarcomatosis is feasible. Preliminary response data suggest prolonged relapse-free survival in some patients. Additional follow-up with more patients will be necessary for full evaluation of the added benefit of PDT and aggressive surgical debulking in these patients.

Hyperbaric oxygen and photodynamic therapy in the treatment of advanced carcinoma of the cardia and the esophagus.

BACKGROUND AND OBJECTIVE: The photochemical reaction of photodynamic therapy (PDT) depends on the presence of molecular oxygen. Because of anoxic regions in tumor tissue and vascular shutdown during PDT, the efficiency is limited. Therefore, the use of hyperbaric oxygen, which increases the oxygen in tumor tissue, as well as the amount of singlet oxygen, may enhance the efficiency of PDT. STUDY DESIGN/MATERIALS AND METHODS: After diagnostic work-up, photosensitization was carried out with a hematoporphyrin-derivate 2 mg/kg body weight 48 hours before PDT. The light dose was calculated as 300 J/cm of fiber tip. Twenty-three patients were treated by PDT alone and 29 patients received PDT under hyperbaric oxygen at a level of two absolute atmospheric pressures. RESULTS: Improvement regarding dysphagia and stenosis-diameter could be obtained in both treatment arms with no significant difference (P = 0.43 and P = 0. 065, respectively). The tumor length also decreased in both groups and showed a significant difference in favour of the PDT/HBO group (P = 0.002). The mean overall survival was 11.3 months. The mean survival time for the PDT group was 8.7 months and for the PDT/HBO group 13.8 months (P = 0.021). CONCLUSION: According to this pilot study, combined PDT/HBO represents a new approach in the treatment of esophageal and cardia cancer, which appears to have enhanced the efficiency of PDT.

Does hyperbaric oxygen enhance the effect of photodynamic therapy in patients with advanced esophageal carcinoma? A clinical pilot study.

BACKGROUND AND STUDY AIMS: Experimental studies have shown that the cytotoxicity of porphyrins and related substances is mediated mainly by singlet oxygen and that hypoxic cells are less affected by porphyrins and light. In a clinical pilot study we assessed the use of photodynamic therapy (PDT) under hyperbaric oxygen (HBO), compared with PDT under normobaric conditions, in patients with advanced esophageal carcinoma. PATIENTS AND METHODS: After diagnostic work-up and staging, photosensitization in all patients was carried out using hematoporphyrine derivate (HpD) (2 mg/kg bodyweight 48 hours prior to PDT). We then applied light at 630 nm (KTP-Nd: YAG laser with DYE box) at dose of 300 J/cm, delivered by a fiber with a radial light-diffusing cylinder (length 1 cm), inserted through the biopsy channel of the endoscope. Of the patients, 14 (12 with stage III cancers, and two with stage IV cancers) were treated by PDT alone, and 17 patients (15 with stage III cancers, and two with stage IV cancers) received PDT under HBO at a level of 2 absolute atmospheric pressures (ATA). Transcutaneous PO2 levels of 500-750 mm Hg under HBO, compared with transcutaneous PO2 levels of 60-75 mm Hg under normobaric conditions, were measured. RESULTS: Improvements regarding dysphagia and stenosis diameter were obtained in both treatment arms with no significant differences (P = 0.36 and 0.14, respectively). The tumor length also decreased in both groups and showed a significant difference in favour of the PDT/ HBO group (P = 0.002). Kaplan-Meier statistics showed median overall survival for the PDT group and the PDT/HBO group as 7.0 and 12 months respectively. The 12-month survival rate was 28.6% for the PDT group and 41.2% for the PDT/HBO group. Logrank test showed a difference in survival in favor of the PDT/HBO group (P = 0.059). No major treatment-related complication occurred, and the 30-day mortality rate was 0%. CONCLUSIONS: Combined PDT/HBO represents a new approach in the treatment of esophageal cancer which, in this pilot study, appears to have enhanced the efficiency of PDT.

Sequencing of combined hyperthermia and photodynamic therapy.

Photodynamic therapy (PDT) and hyperthermia are two alternative tumor treatment modalities currently being investigated in clinical trials. It has been suggested that, due to the differences in cell-killing mechanisms, synergetic tumor responses may be achieved if the two modalities are combined in appropriate sequences. This hypothesis is tested in the current study by delivering graded PDT doses during a transient tumor reoxygenation period after a hyperthermia treatment, or delivering graded hyperthermia doses when the tumor becomes acidic and hypoxic after a PDT treatment. The results indicate that the latter combination sequence has a profound effect on tumor response. While treating the tumors with PDT followed by hyperthermia evokes a synergetic tumor response, reversing the sequence results only in an additive effect. Possible mechanisms associated with tissue oxygenation are discussed.

Experimental study of combined hyperthermic and photodynamic therapy on carcinoma in the mouse.

PURPOSE: This study investigates the cytotoxic effect of photodynamic therapy using high-power laser irradiation on cancer cells. MATERIALS AND METHODS: High- or low-power irradiation from a pulsed Nd:YAG dye laser with or without a photosensitizer was administered to an NR-S1 carcinoma in the mouse dorsum. RESULTS: Photodynamic therapy with high-power laser irradiation yielded better results than conventional photodynamic therapy or hyperthermia with high-power laser irradiation. CONCLUSION: Photodynamic therapy with high-power laser irradiation is more effective because it generates both a hyperthermic and a photodynamic effect.

The effect of hypothermia and hyperthermia on photodynamic therapy of normal brain.

The effect of whole body hyperthermia and hypothermia in conjunction with photodynamic therapy (PDT) was determined on normal rat brain. Hyperthermia animals (Group I, n = 18) were warmed until their core body temperature reached 40 degrees C, (brain temperature, 39.7 +/- 0.5 degree C) and maintained at 40 +/- 1 degree C for 30 minutes prior to and after PDT. Hypothermia (Group II, n = 31) animals were cooled to 30 +/- 1 degree C (brain temperature, 29.3 +/- 0.4 degree C) for 1 hour. PDT treatment was performed, and the body temperature of the animals was maintained at 30 degrees C for 2 hours post-PDT. A population of animals was subjected to PDT under normothermic (Group III, n = 16; body temperature, 37 +/- 1 degree C; brain temperature, 36.7 +/- 0.8 degree C) conditions and treated in a manner identical to that of hyperthermic animals. PDT was performed with 17 J/cm2, 35 J/cm2, or 70 J/cm2 (100 mW/cm2). Photofrin (Quadralogic Technologies Ltd., Vancouver, Canada) (12.5 mg/kg) was injected intraperitoneally 48 hours prior to laser treatment on all three groups. Wet-dry weight measurements were obtained on a separate set of all three groups of animals (n = 27). Cortical lesion depths were measured, and pathological evaluation was made at 24 hours post-PDT. No difference in the wet-dry weight measurements or histopathology was present between the three groups of animals. Lesion depths for Group I animals did not significantly differ from Group III animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of photodynamic therapy-induced heating of hamster melanoma and its effect on local tumour eradication.

To investigate the contribution of hyperthermia on local tumour eradication by photodynamic therapy (PDT) we quantified PDT induced tumour heating and evaluated its biological effect in vivo. Syrian Golden hamsters bearing an amelanotic melanoma implanted into the dorsal skin received intravenous injections of Photofrin (5 mg kg-1). Twenty-four hours later tumours were illuminated by red light (630 nm; total energy: 100 J cm-2) at 100 and 200 mW cm-2 and tumour surface and tumour centre temperature were measured. The tumoricidally threshold temperature of 43 degrees C was exceeded at 200 mW cm-2 only, revealing a calculated equivalent treatment time at 43 degrees C of about 10 min. Melanomas treated by PDT at both light intensities disappeared within 48 h and did not reappear locally within the observation period of 32 days. Tumours treated by hyperthermia (water bath) at the maximum temperatures measured during illumination at 200 mW cm-2 (45.5 degrees C for 500 s) or animals receiving laser light at 200 mW cm-2 alone showed a significant growth delay compared to controls (p < 0.05), whereas illumination at 100 mW cm-2 alone or hyperthermia corresponding to the maximum temperature obtained at 100 mW cm-2 (39.5 degrees C for 1000 s) did not alter tumour growth. These data indicate that tumour temperature increased during PDT and exceeded the hyperthermic threshold temperature of 43 degrees C at 200 mW cm-2. In our tumour model hyperthermia was not necessary for a complete tumour eradication by PDT. Although a combination of PDT and hyperthermia might act in an additive or synergistic manner, an unrecognized overlap of both effects might complicate the interpretation of studies on the mechanisms of PDT.

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.