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ABSTRACT: The cutaneous phototoxic reaction induced by intravenous injection of 5,-10,-15,-20-tetra(m-hydroxyphenyl)chlorin (mTHPC) has been clinically evaluated in patients undergoing photodynamic therapy. These tests were performed on the backs of 23 patients with a solar simulator at various times after drug administration ranging from 5 h to 57 days. The mTHPC doses ranged from 0.1 to 0.3 mg/kg, and the illuminations lasted from 30 s up to 8 min. These tests have shown that the duration of the skin photosensitization induced after a typical therapeutic dose of mTHPC (0.15 mg/kg) is less important than with Photofrin (2 mg/kg). The level of mTHPC in the skin was also assessed in vivo and at times corresponding to the irradiations using an optical fiber-based spectrofluorometer. This study indicates that the light-induced fluorescence spectroscopy of mTHPC enables prediction of the degree of photosensitivity of the skin.
Photochemistry and Photobiology 10/1998; 68(3):382-7. · 2.41 Impact Factor
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ABSTRACT: Patients with cancers of the head and neck have a strong tendency to develop early synchronous and metachronous carcinomas of the esophagus. In many of these patients, whose general condition is poor as a result of alcohol and tobacco abuse, the second primary cancers require minimally invasive treatment. The aims of this study were to evaluate the efficacy of photodynamic therapy for the treatment of early esophageal carcinomas and to compare the results obtained with three different photosensitizers (hematoporphyrin derivative), porfimer sodium (Photofrin II), and meta-(tetrahydroxyphenyl)chlorin (m-THPC).
Thirty-one early squamous cell carcinomas (Tis or T1a) of the esophagus were treated by photodynamic therapy in 24 patients. Nine tumors were treated with hematoporphyrin derivative, eight with Photofrin II and 14 with m-THPC.
The early cancers were cured in 84% of patients after a mean follow-up period of 2 years. Because the number of cases included in each group was small, the differences in recurrence rates for the different photosensitizers could not be evaluated statistically, but m-THPC was more phototoxic, induced a shorter period of photosensitization of the skin, and had better selectivity than either of the other photosensitizers. There were four major complications: two stenoses and two esophagotracheal fistulas.
Photodynamic therapy eradicates early squamous cell carcinomas (Tis and T1a) of the esophagus efficiently. Transmural necroses leading to fistulas can be avoided by using a low-penetrating wavelength of laser light (green light at 514.5 m instead of red light at 630 or 652 nm). Stenoses always result from circumferential irradiation of the esophageal wall, and this can be avoided by using a 180 degrees or 240 degrees windowed cylindrical light distributor.
Endoscopy 04/1998; 30(3):258-65. · 5.21 Impact Factor
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ABSTRACT: Photodynamic therapy (PDT) is an efficient technique to treat superficial early cancers in the pharynx, esophagus, and tracheo-bronchial tree. However, the lack of selectivity of some of the clinically used photosensitizers can result in significant damage to the healthy tissue during the treatment. In the esophagus, this may lead to medical complications such as stenosis and fistula. Insufficient selectivity may be compensated to some extent by accurate light dosimetry. Here, we present an approach to safer and more efficient PDT by improved light dosimetry in the esophagus.
This includes the utilization of a suitable light distributor, the estimation of the radiant energy density in the tissue, and the knowledge of the esophagus morphology. The light distributor presently used in the clinic is described and several techniques to study light propagation in the esophageal wall have been investigated and are discussed. Thickness of different histological layers of the esophageal wall have been measured ex vivo and are presented.
Under these conditions and based on a simple model of the light distribution in the tissue, some basic and clinically useful notions of light dosimetry can be drawn. These notions, associated with measured value of tissue optical properties at the wavelengths of interest with the presently used photosensitizers, are discussed regarding the particular morphology of the esophageal wall. In particular, the importance of the illumination wavelength from the safety point of view is shown.
The proposed approach allows for improved safety and efficacy of PDT in the esophagus, particularly in the clinical tests of new photosensitizers.
Lasers in Surgery and Medicine 02/1997; 20(3):290-303. · 2.75 Impact Factor
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ABSTRACT: A technique to manufacture a stable, reproducible three-dimensional optical phantom is presented. This phantom reproduces the tissue's optical properties as well as the geometry and, to some extent, the mechanical properties of the organ concerned. Easy to make and to handle, this phantom is a useful tool for numerous medical applications involving light interaction with biological tissues.
The phantom is based on a transparent two-component silicone, which is molded into the desired shape and cured at room temperature. Specific optical properties are obtained by adding scatterers (Al2O3 particles or polystyrene microspheres) and absorbers (dyes or pigments). A method to measure the radiant energy fluence rate in the phantom is described. This method is based on a small isotropic optical detector.
A three-dimensional phantom of the bronchial tree is presented. This phantom is used for testing new light distributors designed for photodynamic therapy of the bronchi.
The proposed technique allows one to produce a stable three-dimensional phantom with accurately predictable optical properties.
Lasers in Surgery and Medicine 02/1997; 21(3):227-34. · 2.75 Impact Factor
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ABSTRACT: To clinically evaluate a new photosensitizer, m-tetra(hydroxyphenyl) chlorin (m-THPC), for the photodynamic therapy of early squamous cell carcinomas of the upper aerodigestive tract.
Phase 1 included evaluation of the innocuousness of the compound after intravenous injection (control of vital parameters and blood analysis before and after injection) and evaluation of the duration of skin photosensitization. Phase 2 included assessment of optimal conditions for treatment (injected dose, drug-light interval, light dose, wavelength, etc), on 33 early squamous cell carcinomas of the mouth, esophagus, and bronchi, with a mean follow-up of 14 months; irradiation tests on healthy and neoplastic mucosae to determine the irradiation conditions that lead to tumor eradication with minimal damage to the surrounding normal mucosa and muscle layers; and localization of the dye in various tissue compartments and cells at different time intervals after the injection of the photosensitizer, by using a fluorescence microscope to analyze 46 biopsy specimens taken during the treatment sessions and 8 resected specimens of early cancers, excised with the carbon dioxide laser.
Endoscopic medical center of an otolaryngology-head and neck surgery department.
Twenty-five patients treated previously for a head and neck cancer with a synchronous or metachronous early second primary cancer. Patients with porphyria were excluded from the trial.
The best results in the bronchi and mouth were obtained with an injected dose of 0.15 mg of m-THPC per kilogram of body weight 4 days before irradiation. The fluence was 7 to 16 J/cm2, and the fluence rate was between 100 and 150 mW/cm2 using red light at 652 nm. In the esophagus, green light at 514 nm is preferred to the red light to avoid fistulas. Optimal irradiation conditions at this wavelength, which was also used in the trachea, were found at a fluence of 75 to 100 J/cm2 and a fluence rate between 70 and 100 mW/cm2. Of 33 lesions treated thus far by photodynamic therapy with m-THPC, 28 show no recurrence with a mean follow-up of 14 months. Photosensitivity to sunlight does not exceed 6 weeks.
m-Tetra(hydroxyphenyl) chlorin is a second-generation photosensitizer that has several significant advantages as compared with the first-generation porphyrin mixtures hematoporphyrin derivative and porfimer sodium (Photofrin II). It is a pure compound that is 100 times more phototoxic at 652 nm and 10 times more photoxic at 514 nm, has better selectivity for early carcinomas, and a shorter duration of skin photosensitivity. The therapeutic results indicate a recurrence rate that is similar to that obtained with Photofrin II, ie, about 15%.
Archives of Otolaryngology - Head and Neck Surgery 02/1997; 123(2):162-8. · 1.63 Impact Factor
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ABSTRACT: The influence of the time interval between dye administration and detection by fluorescence microscopy was assessed in "early" squamous cell carcinomas of the cheek pouch mucosa and different healthy tissues of the Syrian hamster. Following intracardiac injection of 0.15 mg (kg bodyweight)-1 of meso-tetra-hydroxyphenylchlorin (m-THPC), groups of three animals were sacrificed at different time intervals up to 30 days. A group of three non-injected animals was used to detect the endogene fluorescence of the corresponding normal tissues for autofluorescence subtraction. The following excised organs (oesophagus, trachea, liver, spleen, kidney, skin, striated muscle, healthy and tumoral cheek pouch mucosae) were fast frozen in liquid nitrogen and stored at -70 degrees C for fluorescence microscopy. The results show significant differences in the detectable m-THPC levels in different tissue layers (for instance, the epithelia and muscle of the oesophagus, trachea and cheek pouch) at different time intervals. These data indicate that pharmacokinetic studies may be useful for selecting the optimal time for the photodetection and phototherapy of cancer.
Journal of Photochemistry and Photobiology B Biology 12/1996; 36(2):143-51. · 2.81 Impact Factor
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ABSTRACT: Under identical conditions (drug and light dose, timing), the results of photodynamic therapy (PDT) of carcinomas of the bronchi with tetra(meta-hydroxyphenyl)chlorin (mTHPC) show large variations between patients. Before patients underwent PDT treatment, the mTHPC level was measured in the lesion, the normal surrounding tissue and the oral cavity, with an apparatus based on fluorescence spectroscopy. The fluctuations in degree of tissue reaction and tumour destruction between patients could be explained by individual variations in the mTHPC level in the mucosa of the bronchi. The patients who showed the highest mTHPC fluorescence signal also had the strongest response to PDT. In addition, a correlation between the mTHPC level in the oral cavity and bronchial mucosa was found. It is concluded that PDT can be improved by measuring the mTHPC level in the bronchi or the oral cavity before treatment by fluorescence spectroscopy, and then by adjusting the light dose to be applied to the observed mTHPC level.
Lasers in Medical Science 11/1996; 11(4):247-254. · 2.00 Impact Factor
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ABSTRACT: A major step in the development of photodynamic therapy (PDT) is the clinical optimization and evaluation of new photosensitizers (PS). Ideally, new compounds should be more effective and/or induce fewer side effects than the first generation PS such as hematoporphyrin derivative and Photofrin. We report the results of our study of PDT applied in the human upper aerodigestive tract, using tetra(m-hydroxyphenyl)chlorin (mTHPC) as the photosensitizing drug. Twenty-seven patients with early (i.e., in situ or microinvasive) squamous cell carcinomas and 4 patients with T1 or T2 cancers were studied. In most cases, illumination of the tumor was performed 4 days after i.v. injection of 0.15 mg/kg of mTHPC using 652 or 514 nm laser light. Of the 36 early tumors evaluated 30 (83%) showed no recurrence after a mean disease-free follow-up of 15.3 months (3-35 months). Of the T1 and T2 cancers, only one achieved a complete response. Major complications, all following red light illuminations, included 1 bronchial stenosis, 1 esophagotracheal fistula, and 2 probable occult perforations of the esophagus. PDT in the esophagus with green light renders such perforations essentially impossible, without, however, reducing the efficacy of the treatment. Skin photosensitization, never observed later than the first week after injection, was seen in 12 patients. In conclusion, photodynamic therapy with mTHPC is a safe and effective technique for the treatment of early carcinomas of the upper aerodigestive tract. Its efficacy is much lower for more advanced cancers.
Journal of Clinical Laser Medicine & Surgery 11/1996; 14(5):281-7.
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ABSTRACT: To test and optimize photodynamic therapy of early cancers in the upper aero-digestive tract and oesophagus, we sought an appropriate animal model, which was found in the 7,12-dimethylbenz[a]anthracene-induced early squamous cell carcinoma in the Golden Syrian hamster. This chemically induced neoplasm is shown, by histology and immunohistochemistry, to pass through similar stages of early cancer development as its human counterpart. Its time sequence is highly reproducible, leading to a well differentiated carcinoma in situ and microinvasive carcinoma in the hamster cheek pouch over a period of 10 weeks.
International Journal of Experimental Pathology 03/1996; 77(1):7-14. · 2.57 Impact Factor
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ABSTRACT: Under standardized conditions (drug and light dose, timing), the result of the photodynamic therapy (PDT) of carcinomas of the esophagus with tetra(meta-hydroxyphenyl)chlorin (mTHPC) shows large variations between patients.
Before patients underwent PDT treatment, the mTHPC level was measured in the lesion, the normal surrounding tissue, and the oral cavity, with an apparatus based on fluorescence spectroscopy.
The fluctuations in degree of tumor destruction between patients can be explained by individual variations in the mTHPC level in the mucosa of the esophagus. The patients showing the highest mTHPC fluorescence signal had also the highest response to PDT. Also, a correlation between the mTHPC level in the oral cavity and esophagus mucosa has been found.
PDT can be improved by measuring the mTHPC level in the esophagus or the oral cavity before treatment by fluorescence spectroscopy, and then by adjusting the light dose to be applied to the observed mTHPC level.
Lasers in Surgery and Medicine 02/1996; 19(3):340-6. · 2.75 Impact Factor
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ABSTRACT: There have been few studies to date of clinical photodynamic therapy (PDT) with tetra(m-hydroxyphenyl)chlorin (mTHPC). This paper describes the results of the authors' experience with this second-generation photosensitizer, used in the treatment of 40 early cancers of the oesophagus and the bronchi. Surface illumination of the tumour was performed, in most cases, 4 days after intravenous injection of 0.15 mg kg–1 of mTHPC, using 652 nm or 514 nm continuous wave laser light. Endoscopic follow-up with biopsies and brushings was possible for 35 tumours: 27 (77%) showed no recurrence after disease-free follow-ups that ranged from 3 to 38 months. Major complications, all of which were after red light illumination, included one bronchial stenosis, one oesophagotracheal fistula and two probable occult perforations of the oesophagus. Photodynamic therapy with green light renders such perforations of the oesophageal wall essentially impossible at the applied conditions, and appears not to reduce the efficacy of the treatment. Skin photosensitization, which was never observed later than the first week after injection, occurred in 12 patients. Hence, PDT with mTHPC is a safe and effective treatment for early carcinomas of the oesophagus and the tracheobronchial tree.
Lasers in Medical Science 01/1996; 11(4):227-235. · 2.00 Impact Factor
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ABSTRACT: To optimize photodynamic therapy (PDT) and photodetection of cancer with second-generation photosensitizers, knowledge of important variables such as the uptake of the dye and the dye contrast between normal and tumoral tissue after injection is necessary. The pharmacokinetics of a second-generation photosensitizer, tetra(meta-hydroxyphenyl)chlorin (mTHPC), is presented. To study this in a clinical context, an apparatus based on fluorescence spectroscopy and a noninvasive optical fiber probe has been used. The mTHPC fluorescence is induced at 2 excitation wavelengths (420 and 520 nm) with different penetration depth. The pharmacokinetics of mTHPC in patients with a squamous-cell carcinoma in the oral cavity show a signal selectivity as high as 16 about 3 hr after i.v. injection for the more advanced carcinomas. The magnitude of this selectivity appears to correlate with the staging of the cancer, the more invasive tumors showing the highest selectivity. Results obtained at 420 and 520 nm show little difference. These pharmacokinetics can be used directly for optimizing photodetection with mTHPC. However, complementary information on the localization of the drug by fluorescence microscopy, and a correlation of this data with tumor necrosis efficacy, are needed to optimize PDT timing.
International Journal of Cancer 11/1995; 63(2):198-204. · 5.44 Impact Factor
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ABSTRACT: In vivo spectrofluorometric anal. during photodynamic therapy (PDT) is a tool to obtain information about fluorophore bleaching kinetics in tissue. Using a cylindrical esophageal light distributor for PDT with an integrated sensing fiber, together with a fluorescence detection setup, the authors can obtain tissue fluorescence spectra endoscopically in a clin. environment. This study was performed on patients with early squamous cell carcinomas in the esophagus. Patients were injected i.v. with 0.15 mg/kg of mTHPC and underwent PDT (l=514 nm, fluence rate = 100 mW/cm2) 96 h after injection. Bleaching kinetics of mTHPC and tissue autofluorescence at different wavelengths were recorded in real time and showed decreases in the obsd. fluorescence intensity in the 652 nm band of about 60 % for light doses around 100 J/cm2. Addnl. information on bleaching kinetics induced at another excitation wavelength, l=652 nm, was obtained by irradiations at much lower doses in the buccal cavity. The data are analyzed using a simplified mechanism in which singlet oxygen is the hypothetical reactive intermediate which can both bleach the mTHPC and the autofluorescent mols. The differential equations are solved by applying the quasi stationary state approxn. for the reactive intermediate. The exptl. data at least do not appear to contradict this oversimplified mechanism.
