Toxicity of photodynamic therapy after combined external beam radiotherapy and intraluminal brachytherapy for carcinoma of the upper aerodigestive tract

BACKGROUND AND OBJECTIVE: To describe the toxicity of photodynamic therapy (PDT) in patients with carcinoma of the upper aerodigestive tract who received prior treatment with external beam irradiation and intraluminal brachytherapy (IB). STUDY DESIGN/MATERIALS AND METHODS: Hospital records of PDT patients were reviewed. Three patients who received prior treatment with external beam irradiation and IB were identified. Two patients had esophageal carcinoma treated with combined chemotherapy and external beam irradiation (55.8 and 50.4 Gy) followed by IB (12 Gy and 35 Gy at 1 cm). These patients then received PDT for treatment of recurrence (2 mg/kg Photofrin injection and 2 light applications: 630 nm, 150--200 J/cm, 200--400 mW/cm). One patient had non-small cell lung cancer treated with external beam irradiation (60 Gy) followed by IB (36.1 Gy at 1 cm) and then received PDT for recurrence (1 mg/kg Photofrin injection and one light application: 630 nm, 150 J/cm, 200 mW/cm). RESULTS: One patient with esophagus cancer had formation of a tracheoesophageal fistula, which required stent placement. The other esophageal cancer patient developed quadriplegia due to an epidural abscess arising from a fistula with the diseased portion of the esophagus. The lung cancer patient had massive hemoptysis after the procedure and died 2 days later. Autopsy showed necrotizing arteritis of the right pulmonary artery. CONCLUSION: Patients with upper aerodigestive tract carcinoma who have received treatment with both external beam irradiation and IB seem to be at higher risk for complications when treated with PDT.     

Photodynamic therapy for human malignant mesothelioma in the nude mouse

Photodynamic therapy (PDT) utilizes a photoactivatable preparation, Photofrin II, which selectively localizes in cancerous tissue and produces substances toxic to that tissue when activated by light. Whether PDT would be able to selectively destroy human malignant mesothelioma was investigated by using a human-derived malignant mesothelioma tumor subcutaneously implanted in nude mice. Human malignant mesothelioma was grown subcutaneously to a size of 0.2-0.4 cm3. Selective retention of Photofrin II was studied by measuring light-induced inhibition of cytochrome c oxidase activity in tumor, heart, and lung. Photofrin II was retained in greater quantities in tumor than in heart or lung at 24 hr after injection. Using laser light at 630 nm under varying conditions, tumor growth was measured every 2 days following PDT for 18 days. All PDT regimens were successful in destroying malignant mesothelioma. Photofrin II at 5 mg/kg was superior to 2 mg/kg (P less than 0.005), light delivered at 50 mW/cm2 x 2 hr was superior to that delivered at 200 mW/cm2 x 30 min (P less than 0.05), and a total fluence of 180 J/cm2 was equivalent to 360 J/cm2 in affecting tumor growth. Ten of 12 mice treated at 50 mW/cm2 became tumor-free and remained so for 30 days following treatment. We concluded that PDT was effective against human malignant mesothelioma in a nude mouse model without adversely affecting the animal. A role for PDT in treating patients with malignant mesothelioma may exist.     

Temporal and illumination-induced variations in the in vivo light transmission spectra of four photosensitizers in EMT6/Ed murine tumours

Temporal and illumination-induced variations in the in vivo light transmission spectrum of the photosensitizer will influence light dosimetry for photodynamic therapy (PDT). The present authors have studied the in vivo spectra of four photosensitizers in the EMT6/Ed murine tumour model in Balb/c mice. The following photosensitizers were used: bis(dimethylthexylsiloxy)silicon 2,3-naphthalocyanine (SiNc 8), benzoporphyrin-derivative monoacid ring A (BPD Verteporfin), Photofrin and ethanolamined hypocrellin B (HBEA-R2). Spectra were measured non-invasively in the EMT6/Ed murine tumour model in the spectral range 600–840 nm, using a diode laser, a dye laser and a Ti:sapphire laser. Red-shift and broadening of the SiNc 8 absorption band was observed at 790 nm, and a slight red-shift was observed in the BPD, HBEA-R2 and Photofrin in vivo absorption spectrum. Exposure to 300 J of light at the peak absorption wavelength caused complete photobleaching of BPD at 690 nm, and a reduced absorption by SiNc 8 at 780 nm, Photofrin at 626 nm, and HBEA-R2 at 656 nm.     

Implications of a pre-existing tumor hypoxic fraction on photodynamic therapy.

The presence of oxygen in tissue is a requirement for photodynamic therapy (PDT)-induced destruction of solid tumors, otherwise no cell death occurs. Since many tumors have been shown to have significant populations of hypoxic cells, it is of clinical interest to determine if pre-existing tumor hypoxia limits phototherapy. This question was examined using RIF tumors where tumor response to PDT of completely oxygenated tumors was compared to tumors with an induced hypoxic fraction. Tumor hypoxia was induced by using vasoactive drugs (epinephrine, chlorpromazine, or isoproterenol), given 30 min prior to PDT, or by a surgical method. PDT consisted of 5 mg/kg Photofrin II ip 24 hr prior to treatment and 135 J/cm2 630-nm light. The administration of the various vasoactive agents induced hypoxic fractions of 2.2 to 10%. The surgical method induced hypoxic fractions of 35%. Tumor response and cure in animals given vasoactive agents did not differ from controls, suggesting that low levels of pre-existing tumor hypoxia do not limit photodynamic therapy in this tumor model. Animals with tumors made hypoxic by a surgical method showed significantly reduced tumor response to PDT. Only 14% of these animals had tumors which became flat and necrotic by the day following PDT, compared to nearly 100% for animals given vasoactive drugs or controls. Furthermore, no tumor cure was observed in animals treated by this method. The higher level of tumor hypoxia in these animals likely represents one point where large proportions of PDT-resistant cells can survive after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vitro and in vivo photosensitizing capabilities of 5-ALA versus photofrin in vascular endothelial cells

BACKGROUND AND OBJECTIVE: The objective of the present study was to evaluate the feasibility of photodynamic therapy (PDT) for complicated hemangiomas. The photosensitizing activities of 5-aminolevulinic acid (5-ALA) and Photofrin were evaluated in vitro with human dermal microvascular endothelial cells (MEC) and in vivo with the chicken cox comb. STUDY DESIGN/MATERIALS AND METHODS: The in vitro absorption and photosensitizing activities of 5-ALA and Photofrin were examined in a MEC culture system. The percentages of MEC killed by different drug concentrations at a wavelength of 630 nm were measured by either live/dead or lactate dehydrogenase-released assays. Similarly, the in vivo biological activities of 5-ALA and Photofrin exposed to different total light dosages at 630 nm were studied by determining the amount of necrosis produced in chicken combs. RESULTS: MEC incubated with 5-ALA at a concentration of 35 microg/ml and exposed to laser light at 630 nm at a power density of 100 mW/cm2 showed a 50% cell kill. MEC incubated with Photofrin at a concentration of 3.5 microg/ml and exposed to laser light at 630 nm at a power density of 100 mW/cm2 showed a 50% cell kill. Chicken combs that received 200 mg/kg of 5-ALA exposed to laser light at 630 nm at a power density of 100 mW/cm2 had an injury depth of 362.5+/-27.6 microm at histologic examination. Combs exposed to a power density of 100 or 120 mW/cm2 showed injury depths of 732.5+/-29.1 and 792.5+/-36.0 microm, respectively. Chicken combs that received 2.5 mg/kg of Photofrin exposed to laser light at 630 nm at a power density of 80 mW/cm2 had an injury depth of 535.6+/-22.3 microm at histologic examination. Combs exposed to a power density of 100 or 120 mW/cm2 showed injury depths of 795.8+/-32.5 and 805.2+/-49.1 microm, respectively. CONCLUSION: Both 5-ALA and Photofrin have the capability to destroy MEC in vitro and vasculature in vivo. However, Photofrin achieved a higher degree of cell kill and tissue destruction at lower drug concentrations and at lower power densities.     

Green light photodynamic therapy in the human bladder

We conducted this pilot clinical study to investigate the safety, primarily acute toxicity, of green light (514.5 nm) whole bladder photodynamic therapy (PDT) in human bladders with transitional cell carcinoma. We enrolled five patients who were scheduled to undergo radical cystectomy and urinary diversion for locally muscle invasive bladder cancer. Four patients received intravenous injection of Photofrin at 1 mg/kg, while one patient received no drug, 48 hr before undergoing green light whole bladder photoactivation with light doses of 20-60 J/cm 2. Each patient underwent radical cystectomy on day 7 following light treatment. Post-PDT evaluation included daily monitoring of voiding symptoms, cystometric measurements of bladder capacity, and gross and histopathologic examination of the excised bladders. Our results show that the intensity of acute bladder irritation and acute post-PDT loss in bladder volume depended on the light dose and extent of bladder tumor with the associated inflammation. There was no transmural bladder injury and no treatment related morbidity. These data on acute toxicity suggest that green light whole bladder PDT treatment with 1 mg/kg of Photofrin and 20-40 J/cm 2 of laser power is safe.     

Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma

PURPOSE: The role of photodynamic therapy (PDT) in the treatment of small cancers has been established in several clinical studies. Here, we report on the efficacy of PDT for early inoperable or recurrent non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: From June 1989 to November 2004, 40 patients with 50 NSCLC were treated with PDT. Twelve cases were inoperable for medical reasons and were staged as T1N0M0, and 28 had recurrent in situ carcinoma. Patients with residual disease after PDT received definitive radiotherapy and/or brachytherapy. Follow-up ranged from 6 to 167 months (median 43.59). Twenty of the 40 patients received i.v. injections of hematoporphyrin derivative (5 mg/kg), the other 20 had injections of porfimer sodium (Photofrin, 2 mg/kg). An argon dye laser (630 nm wavelength, 200-300 J/cm2) was used for light irradiation in 24 of the 40 patients, a diode laser (Diomed, 630 nm wavelength, 100-200 J/cm2) in the other 16. RESULTS: PDT obtained a 72% complete response (CR) rate (36/50 treated lesions), that is 27 CR among the 37 Tis carcinomas and 9 among the 13 T1 cases. Kaplan-Meier curves showed a mean overall survival (OS) of 75.59 months (median 91.4 months). Two- and 5-year OS rates were 72.78% and 59.55%. The mean and median survival rates for patients with Tis stage were 86.5 and 120.4 months, respectively (standard error 9.50) and for patients with T1 disease they were 45.78 and 35.71 months, respectively; the difference was statistically significant (P = 0.03). No severe early or late PDT-related adverse events were recorded. CONCLUSIONS: PDT is effective in early primary or recurrent NSCLC, resulting in a CR rate of 72%. The incorporation of PDT in standard clinical practice, in combination with radiotherapy, warrants further investigation.     

2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) in a nude rat glioma model: implications for photodynamic therapy

BACKGROUND AND OBJECTIVE: In this study, we evaluated 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-alpha (HPPH or Photochlor) as a photosensitizer for the treatment of malignant gliomas by photodynamic therapy (PDT). STUDY DESIGN/MATERIALS AND METHODS: We performed in vivo reflection spectroscopy in athymic rats to measure the attenuation of light in normal brain tissue. We also studied HPPH pharmacokinetics and PDT effects in nude rats with brain tumors derived from stereotactically implanted U87 human glioma cells. Rats implanted with tumors were sacrificed at designated time points to determine the pharmacokinetics of HPPH in serum, tumor, normal brain, and brain adjacent to tumor (BAT). HPPH concentrations in normal brain, BAT and tumor were determined using fluorescence spectroscopy. Twenty-four hours after intravenous injection of HPPH, we administered interstitial PDT treatment at a wavelength of 665 nm. Light was given in doses of 3.5, 7.5 or 15 J/cm at the tumor site and at a rate of 50 mW/cm. RESULTS: In vivo spectroscopy of normal brain tissue showed that the attenuation depth of 665 nm light is approximately 30% greater than that of 630 nm light used to activate Photofrin, which is currently being evaluated for PDT as an adjuvant to surgery for malignant gliomas. The t1/2 of disappearance of drug from serum and tumor was 25 and 30 hours, respectively. CONCLUSION: Twenty-four hours after injection of 0.5 mg/kg HPPH, tumor-to-brain drug ratios ranged from 5:1 to 15:1. Enhanced survival was observed in each of the HPPH/PDT-treated animal groups. These data suggest that HPPH may be a useful adjuvant for the treatment of malignant gliomas.     

Photodynamic therapy with PAD-S31, a new hydrophilic chlorin photosensitizer, in an orthotopic rat bladder tumor model

PURPOSE: PAD-S31 (13,17-bis (1-carboxypropion) carbamoylethyl-3-ethenyl-8-ethoxyiminoethylidene-7-hydroxy-2,7,12,18-tetramethyl-porphyrin sodium) (Photochemical Co., Ltd., Okayama, Japan), 1 of the latest second-generation photosensitizers, has hydrophilic characteristics and excitation wavelengths of around 670 nm. Using an orthotopic rat bladder tumor model we investigated the biodistribution of PAD-S31 and assessed the antitumor effects of photodynamic therapy (PDT) with PAD-S31. MATERIALS AND METHODS: An orthotopic rat bladder tumor was established by implanting AY-27 cells in the bladder wall. After intravenous PAD-S31 administration the accumulation of PAD-S31 in the tumor and normal bladder wall was investigated by a fluorometric technique. One or 3 hours after intravenous administration of PAD-S31 (5 mg/kg) bladder tumors in rats were transurethrally irradiated at 100 mW/cm with a light dose of 50 to 200 J/cm. The efficacy of PDT was evaluated 7 days later by observation with an ultrathin cystoscope and histopathological examination. RESULTS: The ratio of PAD-S31 concentration in tumor tissue to that in normal bladder wall was more than 1 at all time points and it achieved a maximum (more than 10) 150 to 240 minutes after PAD-S31 administration. All rats that were irradiated at 100 J/cm 3 hours after PAD-S31 administration showed more than 50% tumor destruction. When the light dose was more than 150 J/cm, more than half of the rats showed complete tumor eradication, of which the average size was 6 mm. CONCLUSIONS: We report that PDT using PAD-S31 is effective for destroying bladder tumors in an orthotopic rat model. These experimental results suggest that this therapy could be a clinically promising method for the treatment of patients with bladder cancer.     

Comparative study of the phototoxicity of two chrolin type photosensitizers, ATX-S10(Na) and verteporfin, on vascular endothelial and retinal pigment epithelial cells

BACKGROUND AND OBJECTIVES: To compare the phototoxicity in photodynamic therapy (PDT) of ATX-S10(Na) and Verteporfin on human microvascular endothelial cells (HMVEC), vascular endothelial cells of monkey choroid and retina (CRVEC), and human retinal pigment epithelial cells (HRPE). STUDY DESIGN/MATERIALS AND METHODS: PDT was performed in two different ways. In short dye-exposure PDT, HMVEC and CRVEC were exposed to each photosensitizer for 5 minutes followed by laser irradiation of 670 nm wavelength for ATX-S10(Na) or 689 nm for Verteporfin without washing out the photosensitizer in the medium. In long dye-exposure PDT, the cells were exposed to photosensitizers for times ranging from 5 minutes to 2 hours, washed out the photosensitizers, followed by laser irradiation in a fresh medium. PDT was performed on HRPE with PDT doses that resulted in damaging 90% of the HMVEC (ED(90)). Phototoxicity was determined by MTS Assay 1 day after PDT. RESULTS: The degree of phototoxicity depended on the dye concentration, laser dose, and dye exposure time. In short dye-exposure PDT on HMVEC with a laser dose of 50 J/cm(2), the ED(90) was 6.3 microg/ml of ATX-S10(Na) and 0.04 microg/ml of Verteporfin, while in long dye-exposure PDT the ED(90) was 50.0 microg/ml of ATX-S10(Na) and 0.04 microg/ml of Verteporfin when the medium was supplemented with 5% fetal calf serum. The phototoxic rate on HMVEC was higher when the medium contained 5% as contrasted with 10% of serum. In short dye-exposure PDT, the ED(90) of CRVEC was 100 microg/ml of ATX-S10(Na) and an irradiance of 100 J/cm(2), and 0.08 microg/ml of Verteporfin and an irradiance of 100 J/cm(2) when the medium was supplemented with 10% serum. With some doses of short dye-exposure PDT, the ATX-S10(Na) achieved higher phototoxic rates on HMVEC and CRVEC than on the HRPE. However, long dye-exposure PDT with ATX-S10(Na) and short and long dye-exposure PDT with Vereteporfin failed to obtain higher phototoxic rates on HMVEC and CRVEC than on HRPE. CONCLUSIONS: Verteporfin had a higher phototoxicity than ATX-S10(Na) on HMVEC and CRVEC. The CRVEC resisted more than HMVEC following PDT with both photosensitizers. In short dye-exposure PDT, ATX-S10(Na) had a more selective phototoxicity on HMVEC and CRVEC than on HRPE.     

Clinical pharmacokinetics of the PDT photosensitizers porfimer sodium (Photofrin), 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (Photochlor) and 5-ALA-induced protoporphyrin IX

BACKGROUND AND OBJECTIVES: Photodynamic therapy (PDT) uses a photosensitizer activated by light, in an oxygen-rich environment, to destroy malignant tumors. Clinical trials of PDT at Roswell Park Cancer Institute (RPCI) use the photosensitizers Photofrin, Photochlor, and 5-ALA-induced protoporphyrin IX (PpIX). In some studies the concentrations of photosensitizer in blood, and occasionally in tumor tissue, were obtained. Pharmacokinetic (PK) data from these individual studies were pooled and analyzed. This is the first published review to compare head-to-head the PK of Photofrin and Photochlor. STUDY DESIGN/MATERIALS AND METHODS: Blood and tissue specimens were obtained from patients undergoing PDT at RPCI. Concentrations of Photofrin, Photochlor, and PpIX were measured using fluorescence analysis. A non-linear mixed effects modeling approach was used to analyze the PK data for Photochlor (up to 4 days post-infusion; two-compartment model) and a simpler multipatient-data-pooling approach was used to model PK data for both Photofrin and Photochlor (at least 150 days post-infusion; three-compartment models). Physiological parameters were standardized to correspond to a standard (70 kg; 1.818 m2 surface area) man to facilitate comparisons between Photofrin and Photochlor. RESULTS: Serum concentration-time profiles obtained for Photofrin and Photochlor showed long circulating half-lives, where both sensitizers could be found more than 3 months after intravenous infusion; however, estimated plasma clearances (standard man) were markedly smaller for Photofrin (25.8 ml/hour) than for Photochlor (84.2 ml/hour). Volumes of distribution of the central compartment (standard man) for both Photofrin and Photochlor were about the size (3.14 L, 4.29 L, respectively) of plasma volume, implying that both photosensitizers are almost 100% bound to serum components. Circulating levels of PpIX were generally quite low, falling below the level of instrument sensitivity within a few days after topical application of 5-ALA. CONCLUSION: We have modeled the PK of Photochlor and Photofrin. PK parameter estimates may, in part, explain the relatively long skin photosensitivity attributed to Photofrin but not Photochlor. Due to the potential impact and limited experimental PK data in the PDT field further clinical studies of photosensitizer kinetics in tumor and normal tissues are warranted.     

Photodynamic therapy of high-grade cervical intraepithelial neoplasia with 5-aminolevulinic acid

BACKGROUND AND OBJECTIVES: To determine the safety and efficacy of 5-aminolevulinic acid (ALA) as a topically applied photosensitizer for photodynamic therapy (PDT) of cervical intraepithelial neoplasia (CIN). STUDY DESIGNS/MATERIALS AND METHODS: Forty women, who were at least 18 years old with persistent biopsy-proven CIN 2 and CIN 3 within the previous 3 months of enrollment, underwent PDT in a phase I and II design. Five escalating radiant energies (increments of 25 J/cm(2), beginning at 50-150 J/cm(2)) using a Coherent Dye Model 920 argon pumped dye laser providing light at 630 nm (maximum output 0.8 W) were used to perform PDT with a fixed dose of ALA (200 mg/ml). ALA was placed in a cervical cap fitted to the cervix. After 90 minutes, the cap was removed and the ectocervix was illuminated for 5-16 minutes, depending on the irradiance. Success was defined as the absence of CIN on Pap smear or colposcopic examination at 12-months. Patients were monitored for toxicity. RESULTS: Thirty-two women (80%) completed the study with 1 year of follow-up. Sixty percent had CIN 3 and 40% CIN 2. Success rates at 4, 8, and 12 months were 51, 46, and 31%, respectively, and were not light-dose dependent. Three patients progressed from CIN 2 to CIN 3. Toxicity was tolerable and only consisted of spotting, vaginal discharge, mild cramping, and vaginal warmth. There was no apparent dose relationship to toxicity. CONCLUSIONS: PDT at this light and ALA dose is well tolerated but has minimal activity in the treatment of CIN 2 and CIN 3. Other doses and schedules of light and ALA or novel photosensitizers may improve efficacy.     

Enhanced cell death in NR-S1 tumor by photodynamic therapy: possible involvement of Fas and Fas ligand system

BACKGROUND AND OBJECTIVES: To investigate the effect of photodynamic therapy (PDT) on cell death in malignant tumor tissue, the frequency of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells and the possible involvement of Fas and Fas ligand system were evaluated. STUDY DESIGN/MATERIALS AND METHODS: NR-S1 tumor-bearing C3H/HeNCrj mice were treated by PDT with Photofrin(R) (12 mg/kg body weight) and Nd:YAG dye laser (630 nm, 10 Hz, 150 J/cm(2)). Paraffin-embedded tissue sections from the excised tumor tissues at 6, 12, 24, 48 hours after PDT were analyzed by TUNEL for the occurrence of apoptosis and by immunohistochemistry for Fas and Fas ligand (FasL) expression. TUNEL-positive cells as well as Fas- or FasL-positive cells were counted and expressed as a percentage of positive cells per total cells. RESULTS: Based on the percent area of tumor necrotic foci, the most effective conditions for PDT were first determined. Under these conditions, PDT increased the number of TUNEL-positive tumor cells at 12 hours after irradiation. In parallel with the increase in TUNEL-positive cells, Fas-positive tumor cells were also found in the same area where many TUNEL-positive tumor cells were found. The expression of Fas ligand was found in the tumor cells surrounding TUNEL-positive cells on serial sections. A significant increase in FasL-positive lymphocytes was observed at 12 hours, whereas the infiltration of such lymphocytes into the area where TUNEL-positive tumor cells were observed was rare. CONCLUSION: The possible role of Fas/FasL system in the cell death induced by PDT with Photofrin(R) and Nd:YAG dye laser was suggested. Moreover, the role of infiltrated lymphocytes seemed not to be so much in this model.     

Combination studies of hyperthermia induced by the neodymium: yttrium-aluminum-garnet (Nd:YAG) laser as an adjuvant to photodynamic therapy

Photodynamic therapy (PDT) and hyperthermia have been investigated as treatments for several types of tumors. Studies have been done to determine the efficacy of each modality individually and recently in combination with each other. In this study, 630-nm light was delivered by an argon-dye laser and hyperthermia was induced using an Nd:YAG laser. Both lasers offer the ability of delivering the beams through a quartz fiberoptic alone or simultaneously. This study examines the efficacy of the simultaneous administration of PDT and selective hyperthermia at 44.5 degrees C in tumor control in the spontaneous mammary tumor (SMT-F) in DBA mice. Hyperthermia alone (44.5 degrees C, 30 min) resulted in complete destruction of tumors, with no subsequent regrowth in 6.6% of the mice treated. PDT alone (5 mg/kg dihematoporphyrin ether; 135 J/cm) resulted in a cure rate of approximately 10%, and the simultaneous treatment of the modalities resulted in a 32.8% cure rate after 90 days. These values are indicative of a synergistic interaction.     

Breast Cancer With Chest Wall Progression: Treatment With Photodynamic Therapy

Background: Chest wall progression of breast carcinoma affects up to 5% of breast cancer patients and is a major source of their pain. Treatment options are limited or may not be offered to these patients. Low-dose Photofrin-induced photodynamic therapy (PDT) offers an excellent clinical response with minimal morbidity. We report our continued experience with PDT in this setting.Methods: Fourteen patients with more than 500 truncal metastases were treated with PDT. All received off-label Photofrin (.8 mg/kg) IV and light treatment at 630 nm from a diode laser with a microlens at a fluence of 1800 mW and a total light dose of 150 to 200 J/cm² at 48 hours. One patient required re-treatment because of extensive disease.Results: Follow-up was at least 6 months, and several extended to >24 months. All patients demonstrated tumor necrosis, with 9 of 14 complete responses, including with lesions >2 cm in thickness. Disease progression occurred outside of the treatment field. Several patients had initial regression of untreated lesions. Wound care, especially with disease in the deep tissues, was an issue.Conclusions: Low-dose Photofrin-induced PDT offers patients with chest wall progression a treatment option with an excellent clinical response. To date, the response is prolonged and offers good local control. Surgical oncologists have an active role in this treatment option.     

Experimental photodynamic therapy for malignant pleural mesothelioma with pegylated mTHPC

BACKGROUND AND OBJECTIVES: Experimental assessment of photodynamic therapy (PDT) for malignant pleural mesothelioma using a polyethylene glycol conjugate of meta-tetrahydroxyphenylchlorin (PEG-mTHPC). STUDY DESIGN/MATERIALS AND METHODS: (a) PDT was tested on H-meso-1 xenografts (652 nm laser light; fluence 10 J/cm(2); 0.93, 9.3, or 27.8 mg/kg of PEG-mTHPC; drug-light intervals 3-8 days). (b) Intraoperative PDT with similar treatment conditions was performed in the chest cavity of minipigs (n = 18) following extrapleural pneumonectomy (EPP) using an optical integrating balloon device combined with in situ light dosimetry. RESULTS: (a) PDT using PEG-mTHPC resulted in larger extent of tumor necrosis than in untreated tumors (P < or = 0.01) without causing damage to normal tissue. (b) Intraoperative PDT following EPP was well tolerated in 17 of 18 animals. Mean fluence and fluence rates measured at four sites of the chest cavity ranged from 10.2 +/- 0.2 to 13.2 +/- 2.3 J/cm(2) and 5.5 +/- 1.2 to 7.9 +/- 1.7 mW/cm(2) (mean +/- SD). Histology 3 months after light delivery revealed no PDT related tissue injury in all but one animal. CONCLUSIONS: PEG-mTHPC mediated PDT showed selective destruction of mesothelioma xenografts without causing damage to intrathoracic organs in pigs at similar treatment conditions. The light delivery system afforded regular light distribution to different parts of the chest cavity.     

Photodynamic therapy of superficial bladder tumors

Photodynamic therapy (PDT), using hematoporphyrin derivative (HPD) and the red light (wavelength 630 nm) of an argon-dye laser as the source of excitation energy was performed on 46 patients with superficial bladder tumors. Two methods of laser irradiation, (1) focal PDT using a 400 micron quartz fiber through a cystourethroscope in 22 patients with superficial bladder tumors and (2) whole bladder wall total PDT using a motor-driven laser light scattering device in 24 patients with multifocal carcinoma in situ and/or dysplasia of bladder mucosa associated with multicentric concurrent superficial tumors, were used. The patients in (2) had been referred for total cystectomy, and 19 of these 24 patients had a history of several transurethral resections, hyperthermia and/or instillation therapy. HPD 2-4 mg/kg was i.v. injected 48 to 72 hours before PDT. Judging from the results of 60 protrusions treated by focal PDT, the light power should be 200 mW/cm2 for 5-10 minutes or more and the total light energy should be 100 J/cm2 or more in tumors up to 2 cm in size. With focal PDT, 4 of the 22 patients had no recurrence with the mean tumor free time of 20.8 months. In 6 of the 24 patients treated with total PDT using 10, 20 or 30 J/cm2 of light energy, there was no recurrence with a mean tumor-free time of 7.5 months and there was no significant relationship between the recurrence rate and total light energy used.     

A multispectral fluorescence imaging system: design and initial clinical tests in intra-operative Photofrin-photodynamic therapy of brain tumors

BACKGROUND AND OBJECTIVES: Intra-operative identification of tumor by fluorescence may improve surgical resection or photodynamic therapy (PDT). A novel instrument was designed, constructed, and tested for this purpose. STUDY DESIGN/MATERIALS AND METHODS: The instrument was designed to provide high-resolution, multi-spectral (five band) fluorescence imaging, and non-contact point spectroscopy, with long working distance ( approximately 50 cm), large field-of-view ( approximately 3 cm diameter), large depth of view ( approximately 2 cm), and 'point-and-shoot' operation. Its performance was determined in tissue-simulating phantoms and in pilot studies in brain tumor resection patients, with or without intra-operative Photofrin-PDT. RESULTS: In phantoms the imaging resolution was approximately 150 microm, while Photofrin concentrations as low as 0.05 or 0.1 microg/g could be detected at the tissue surface or at 0.5 mm depth, respectively. Red Photofrin fluorescence could be clearly visualized post radical resection in all PDT patients, with biopsy confirmation of residual tumor tissue in regions that were not seen as tumor under white light. Photobleaching of Photofrin during PDT was also demonstrated. CONCLUSIONS: The system performed to specification under realistic operating conditions and could reveal unresected residual tumor tissue. It may be used for either PDT dosimetry/monitoring and/or for surgical guidance.     

Microvascular blood flow dynamics associated with photodynamic therapy, pulsed dye laser irradiation and combined regimens

BACKGROUND AND OBJECTIVES: Previous in vitro studies demonstrated the potential utility of benzoporphyrin derivative monoacid ring A (BPD) photodynamic therapy (PDT) for vascular destruction. Moreover, the effects of PDT were enhanced when this intervention was followed immediately by pulsed dye laser (PDL) irradiation (PDT/PDL). We further evaluate vascular effects of PDT alone, PDL alone and PDT/PDL in an in vivo rodent dorsal skinfold model. STUDY DESIGN/MATERIALS AND METHODS: A dorsal skinfold window chamber was installed surgically on female Sprague-Dawley rats. One milligram per kilogram of BPD solution was administered intravenously via a jugular venous catheter. Evaluated interventions were: control (no BPD, no light), PDT alone (576 nm, 16 minutes exposure time, 15 minutes post-BPD injection, 10 mm spot), PDL alone at 7 J/cm2 (585 nm, 1.5 ms pulse duration, 7 mm spot), PDL alone at 10 J/cm2, PDT/PDL (PDL at 7 J/cm2), and PDT/PDL (PDL at 10 J/cm2). To assess changes in microvascular blood flow, laser speckle imaging was performed before, immediately after, and 18 hours post-intervention. RESULTS: Epidermal irradiation was accomplished without blistering, scabbing or ulceration. A reduction in perfusion was achieved in all intervention groups. PDT/PDL at 7 J/cm2 resulted in the greatest reduction in vascular perfusion (56%). CONCLUSIONS: BPD PDT can achieve safe and selective vascular flow reduction. PDT/PDL can enhance diminution of microvascular blood flow. Our results suggest that PDT and PDT/PDL should be evaluated as alternative therapeutic options for treatment of hypervascular skin lesions including port wine stain birthmarks.     

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

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