122
6 7 8
9 10
11 12
13
NEWS AND VIEWS
comeal endothelial cell function and ultra-structure, Invest. OphthaZmol. Vis. Sci., 26 (1985) 1465-1474. J. E. Roberts, D. Roy and J. Dillon, The photosensitized oxidation of the calf lens MIP (MP 26) with HPD, Curr. Eye Res., 4 (1985) 181-185. F. Khanurn and V. Jain, Effects of HPD on the cellular energy metabolism in the absence and presence of light, Photo&em. Photobiol., 50 (1989) 647-651. J. A. Panagopoulos, P. P. Svitra, C. A. P-uliafitoand E. S. Gragoudas, Photodynamic therapy for experimental intraocular melanoma using Chloroaluminum Sulfonated Phthalocyanine, Arch. Ophthalwwl., IO7 (1989) 886-890. J. D. Spikes, Phthalocyanines as photosensitizers in biologic systems and for the photodynamic therapy of tumors, Photo&em., PhotobioZ., 43 (1986) l-9. K. Winward, C. K. Dabbes, K. Olsen, B. D. Watson, E. Hernandez and C. DiBemardo, Encircling photothrombotic therapy for choroidal green melanoma using rose bengal, Arch. Ophthalmol., 108 (1990) 588-594. R. A. Bruce, Evaluation of HPDPRT to treat choroidal melanomas, Lasers Surg. Med., 4 (1984) 59-64. D. Char, J. R. Castro, S. M. Kroll, A. R. Irvine, J. M. Quivey and R. D. Stone, Five year follow-up of helium ion therapy for uveal melanoma, Arch. Ophthalnml., 108 (1990) 209-214. W. Benedict, R. W. Lingua, D. R. Doiron, J. A. Dawson and A. L. Mu&tree, Tumor regression in the nude mouse following photoradiation therapy - a preliminary report, J. Pediatr. Oncol., 8 (1980) 397-401.
Potential of photodynamic therapy in the treatment of pharyngeal tumours: the clinical point of view Ph. Monnier Department of Otmhinolaryngology, Lausanne (Switzerland]
Centre Hospital&r
Univmsitaire
Vaudois,
As in any other hollow organ of the body, photodynamic therapy (PDT) should only be used for the treatment of early (superficial) cancers in the pharynx. A cancerous infiltration of the whole thickness of the organ wall, as is often seen in advanced carcinomas, would lead to severe complications such as perforation if PDT is to be efficient in destroying the tumour completely. In the case of a cancerous infiltration of the cartilaginous framework of the larynx from a pharyngeal tumour, there is no hope for cure with PDT. For ethical reasons, most clinical studies have dealt with the palliative PDT of inoperable cancers in the oesophagus or in the bronchi; however there is no place for such a treatment in the pharynx, where a surgical resection and immediate reconstruction are always possible with acceptable morbidity and mortality. Whatever the future potential of PDT may be with better photosensitizers and better light do&retry, it must be realized that rapid destruction of a large tumour in the aero-digestive tract by any means leads to complications if no simultaneous reconstruction is undertaken. At the present time, only
NJZWSANDVEWS
123
surgery is capable of doing both. The only site where one could consider treating a fairly large tumour volume with interstitial PDT in the pharynx is the base of the tongue, but this is still unethical because better treatment modalities exist for this tumour site.
1. Early
(superficial)
cancers
of the pharynx
In the upper aero-digestive tract, carcinogenesis is characterized by a “field cancerization” leading to the multicentricity of lesions [ 11. In a retrospective analysis of 115 early pharyngeal carcinomas resected and submitted to serial histological sections, 83% displayed multicentric foci of dysplasia, carcinoma in situ and microinvasive carcinoma [ 21. A surface extension of a few square centimetres is a common feature in early cancers of the upper digestive tract, whereas the in-depth invasion remains limited to less than 1 or 2 mm. Theoretically, this should represent an ideal situation for PDT, but three main problems need to be solved before this treatment modality may be considered safe for the patient. (i) An exact knowledge of the in-depth invasion of a superficial cancer prior to any treatment. (ii) The possibility of irradiating the whole tumour homogeneously. (iii) The development of more selective and more stable photosensitizers than haematoporphyrin derivative (HPD) or dihaematoporphyrin ether/ester (DHE). 1.1. In-depth invasion of supe~@5ul cancers Although endoscopic ultrasonography has been used with some success in the digestive tract for assessing the in-depth invasion of carcinomas [ 31, it still does not allow a clear differentiation between intramucosal and submucosal cancers in the pharyngo-oesophageal region. In the digestive tract lined with squamous cell mucosa, we have conducted a prospective study based on morphological and morphometric criteria to evaluate the degree of in-depth invasion of early cancers during endoscopy [4]. The endoscopist establishes a visual histological staging of the early cancer (based on mucosal colour modifications and localization and surface extension of the lesion after tolmdine blue staining) and notifies by a secret score whether the lesion is judged dysplastic, in situ, microinvasive or invasive (in-depth invasion of more than 1 mm). After an in toto excision of the lesion, the fmal diagnosis is established by serial histological sections, the pathologist being Unaware of the code used for scoring the early cancer at endoscopy. The error demonstrated by the false negative results (underestimated invasion) was only 4% in a series of 80 cases. This means that any tumour depth profiling device (endoscopic ultrasonography, laser systems, etc.) should be at least as accurate as the visual judgement of a good endoscopist.
124
NEWS AND VIEWS
We are currently developing a new method for endoscopic tumour depth profiling, using tumour-localizing dyes that can be induced to fluoresce at three wavelengths in the visible. The principle of this method is based on the changing penetration depth of light in tissue with varying wavelengths. The fluorescing dye which is taken up selectively by the tumour luminesces at 690 run after excitation at all three wavelengths. The ratio of the fluorescence yields from the tissue at the three wavelengths depends on the tumour depth of a given geometry. Preliminary tests on realistic tumour phantoms loaded with HPD are encouraging for profiling up to 4 mm, but, of course, the more selective the concentration of the dye within the tumour, the more effective the device. 1.2. Homogeneous light distribution on the tumour site Although much more information needs to be gathered on light absorption at different wavelengths by different living tissues, a fairly homogeneous light distribution may be obtained by using a light di&sing cylinder in a tubular organ such as the oesophagus [5]. In the pharynx, however, the anatomy is characterized by the presence of many folds and recesses. This complex geometry is far more complicated than that of the urinary bladder, and precludes any attempt at a complete irradiation of the whole pharynx with the lack of tumour selectivity encountered with dyes of the iirst generation (HPD and DHE). This would lead to extensive superficial necrosis of normal mucosa and subsequent scarring and stricture. It must be remembered that a superficial pharyngeal cancer extending several square centimetres over the surface may appear at the same time tangential and perpendicular to the light source, whether it be a cylinder or a frontal irradiator. In our clinical experience with PDT of 50 early squamous cell carcinomas of the pharynx, oesophagus and bronchi [ 51, we achieved the worst cure rates in the pharynx. This was clearly due to difficulties in obtaining a homogeneous light distribution over the whole surface of the lesions. Only early cancers strictly located to the pyriform sinus or to the posterior wall of the pharynx may be irradiated using a light diffusing cylinder at the present time. However, the ilnal goal to be achieved, when more selective photosensitizers become available, is a homogeneous irradiation of the whole pharynx by means of a diifusing solution or substance. 1.3. New photosensitizers The necrosis induced by PDT with HPD or DHE is largely sufhcient for destroying early cancers, but unfortunately, it is not selective at all in the digestive tract lined with squamous cell mucosa or in the trachea-bronchial tree [ 5). This implies the use of fenestrated irradiating cylinders to avoid circular necrosis and subsequent stenosis. Extensive research is under way to llnd more selective and more stable photosensitizers than HPD and DHE. In the near future, zinc phthalocysnines embedded in liposomes and benzoporphyrin derivative will be used for phase I clinical trials in the U.S.A. and Europe. Prom a clinical point of view, it
NEWS AND VIEWS
125
is clear that, without better dyes than DHE, there is no future for PDT in the upper aero-digestive tract, and in other hollow organs.
2. Conclusions In addition to the common problems encountered with PDT (lack of selectivity of HPD or DHE, skin photosensitivity, problems with accurate tumour depth profiling, etc.), the greatest challenge in treating early pharyngeal carcinomas is the actual impossibility of irradiating the whole lesion homogeneously, except for small lesions located to the pyriform sinuses or to the posterior wall. If the future hope is to apply this treatment modality routinely in oncology, we need to address the following problems: (i) find more selective, more stable photosensitizers with reasonable phototoxicity; (ii) solve the problem of accurately determining the in-depth invasion of early cancers prior to any treatment; (iii) obtain a better knowledge of the patterns of diffusion and absorption of light in different living tissues at different wavelengths; (iv) find light diffusing media (solutions, pastes, etc.) for complex anatomical geometries (pharynx, bronchi) with acceptable light scattering properties and as little loss of transmission as possible. These are great challenges indeed, but they should stimulate alIresearchers from the basic sciences to the clinical applications. Only then can we hopefully see this new treatment modality being widely accepted in the armamentarium against some types of cancers. 1 D. P. Slaughter, H. W. Southwick and W. Smejkal, “Field cancerisation” in oral stratilIed squamous epithelium, Cancer, 6 (1953) 963-968. 2 Ph. Monnier, Le carcinome epidermdide “precoce” de la voie digestive superieure, Th&e de Doctor-at, Lausanne, 1986. 3 T. L. Tio and G. N. J. Qtgat, Atlas of 5’kcmsimstid ultmsonographg, Smith Kline and French, Rijswijk, 1986. 4 Ph. Pasche, Le staging endoscopique du cancer precoce pour la voie digestive superieure, Aktuel. Probl. Otorhinolargngol., 12 (1988) 131-137. 5 Ph. Monnier, M. Savary, Ch. Fontolliet, G. Wagmeres, A. Chatelain, P. Comas, Ch. Depeursinge and H. Van den Bergh, Photodetection and photodynamic therapy of “early” squamous cell carcinomas of the pharynx, oesophagus and trachea-bronchial tree, Lasers Med. Sci., 5 (1990) 149-169.
6 7 8
9 10
11 12
13
NEWS AND VIEWS
comeal endothelial cell function and ultra-structure, Invest. OphthaZmol. Vis. Sci., 26 (1985) 1465-1474. J. E. Roberts, D. Roy and J. Dillon, The photosensitized oxidation of the calf lens MIP (MP 26) with HPD, Curr. Eye Res., 4 (1985) 181-185. F. Khanurn and V. Jain, Effects of HPD on the cellular energy metabolism in the absence and presence of light, Photo&em. Photobiol., 50 (1989) 647-651. J. A. Panagopoulos, P. P. Svitra, C. A. P-uliafitoand E. S. Gragoudas, Photodynamic therapy for experimental intraocular melanoma using Chloroaluminum Sulfonated Phthalocyanine, Arch. Ophthalwwl., IO7 (1989) 886-890. J. D. Spikes, Phthalocyanines as photosensitizers in biologic systems and for the photodynamic therapy of tumors, Photo&em., PhotobioZ., 43 (1986) l-9. K. Winward, C. K. Dabbes, K. Olsen, B. D. Watson, E. Hernandez and C. DiBemardo, Encircling photothrombotic therapy for choroidal green melanoma using rose bengal, Arch. Ophthalmol., 108 (1990) 588-594. R. A. Bruce, Evaluation of HPDPRT to treat choroidal melanomas, Lasers Surg. Med., 4 (1984) 59-64. D. Char, J. R. Castro, S. M. Kroll, A. R. Irvine, J. M. Quivey and R. D. Stone, Five year follow-up of helium ion therapy for uveal melanoma, Arch. Ophthalnml., 108 (1990) 209-214. W. Benedict, R. W. Lingua, D. R. Doiron, J. A. Dawson and A. L. Mu&tree, Tumor regression in the nude mouse following photoradiation therapy - a preliminary report, J. Pediatr. Oncol., 8 (1980) 397-401.
Potential of photodynamic therapy in the treatment of pharyngeal tumours: the clinical point of view Ph. Monnier Department of Otmhinolaryngology, Lausanne (Switzerland]
Centre Hospital&r
Univmsitaire
Vaudois,
As in any other hollow organ of the body, photodynamic therapy (PDT) should only be used for the treatment of early (superficial) cancers in the pharynx. A cancerous infiltration of the whole thickness of the organ wall, as is often seen in advanced carcinomas, would lead to severe complications such as perforation if PDT is to be efficient in destroying the tumour completely. In the case of a cancerous infiltration of the cartilaginous framework of the larynx from a pharyngeal tumour, there is no hope for cure with PDT. For ethical reasons, most clinical studies have dealt with the palliative PDT of inoperable cancers in the oesophagus or in the bronchi; however there is no place for such a treatment in the pharynx, where a surgical resection and immediate reconstruction are always possible with acceptable morbidity and mortality. Whatever the future potential of PDT may be with better photosensitizers and better light do&retry, it must be realized that rapid destruction of a large tumour in the aero-digestive tract by any means leads to complications if no simultaneous reconstruction is undertaken. At the present time, only
NJZWSANDVEWS
123
surgery is capable of doing both. The only site where one could consider treating a fairly large tumour volume with interstitial PDT in the pharynx is the base of the tongue, but this is still unethical because better treatment modalities exist for this tumour site.
1. Early
(superficial)
cancers
of the pharynx
In the upper aero-digestive tract, carcinogenesis is characterized by a “field cancerization” leading to the multicentricity of lesions [ 11. In a retrospective analysis of 115 early pharyngeal carcinomas resected and submitted to serial histological sections, 83% displayed multicentric foci of dysplasia, carcinoma in situ and microinvasive carcinoma [ 21. A surface extension of a few square centimetres is a common feature in early cancers of the upper digestive tract, whereas the in-depth invasion remains limited to less than 1 or 2 mm. Theoretically, this should represent an ideal situation for PDT, but three main problems need to be solved before this treatment modality may be considered safe for the patient. (i) An exact knowledge of the in-depth invasion of a superficial cancer prior to any treatment. (ii) The possibility of irradiating the whole tumour homogeneously. (iii) The development of more selective and more stable photosensitizers than haematoporphyrin derivative (HPD) or dihaematoporphyrin ether/ester (DHE). 1.1. In-depth invasion of supe~@5ul cancers Although endoscopic ultrasonography has been used with some success in the digestive tract for assessing the in-depth invasion of carcinomas [ 31, it still does not allow a clear differentiation between intramucosal and submucosal cancers in the pharyngo-oesophageal region. In the digestive tract lined with squamous cell mucosa, we have conducted a prospective study based on morphological and morphometric criteria to evaluate the degree of in-depth invasion of early cancers during endoscopy [4]. The endoscopist establishes a visual histological staging of the early cancer (based on mucosal colour modifications and localization and surface extension of the lesion after tolmdine blue staining) and notifies by a secret score whether the lesion is judged dysplastic, in situ, microinvasive or invasive (in-depth invasion of more than 1 mm). After an in toto excision of the lesion, the fmal diagnosis is established by serial histological sections, the pathologist being Unaware of the code used for scoring the early cancer at endoscopy. The error demonstrated by the false negative results (underestimated invasion) was only 4% in a series of 80 cases. This means that any tumour depth profiling device (endoscopic ultrasonography, laser systems, etc.) should be at least as accurate as the visual judgement of a good endoscopist.
124
NEWS AND VIEWS
We are currently developing a new method for endoscopic tumour depth profiling, using tumour-localizing dyes that can be induced to fluoresce at three wavelengths in the visible. The principle of this method is based on the changing penetration depth of light in tissue with varying wavelengths. The fluorescing dye which is taken up selectively by the tumour luminesces at 690 run after excitation at all three wavelengths. The ratio of the fluorescence yields from the tissue at the three wavelengths depends on the tumour depth of a given geometry. Preliminary tests on realistic tumour phantoms loaded with HPD are encouraging for profiling up to 4 mm, but, of course, the more selective the concentration of the dye within the tumour, the more effective the device. 1.2. Homogeneous light distribution on the tumour site Although much more information needs to be gathered on light absorption at different wavelengths by different living tissues, a fairly homogeneous light distribution may be obtained by using a light di&sing cylinder in a tubular organ such as the oesophagus [5]. In the pharynx, however, the anatomy is characterized by the presence of many folds and recesses. This complex geometry is far more complicated than that of the urinary bladder, and precludes any attempt at a complete irradiation of the whole pharynx with the lack of tumour selectivity encountered with dyes of the iirst generation (HPD and DHE). This would lead to extensive superficial necrosis of normal mucosa and subsequent scarring and stricture. It must be remembered that a superficial pharyngeal cancer extending several square centimetres over the surface may appear at the same time tangential and perpendicular to the light source, whether it be a cylinder or a frontal irradiator. In our clinical experience with PDT of 50 early squamous cell carcinomas of the pharynx, oesophagus and bronchi [ 51, we achieved the worst cure rates in the pharynx. This was clearly due to difficulties in obtaining a homogeneous light distribution over the whole surface of the lesions. Only early cancers strictly located to the pyriform sinus or to the posterior wall of the pharynx may be irradiated using a light diffusing cylinder at the present time. However, the ilnal goal to be achieved, when more selective photosensitizers become available, is a homogeneous irradiation of the whole pharynx by means of a diifusing solution or substance. 1.3. New photosensitizers The necrosis induced by PDT with HPD or DHE is largely sufhcient for destroying early cancers, but unfortunately, it is not selective at all in the digestive tract lined with squamous cell mucosa or in the trachea-bronchial tree [ 5). This implies the use of fenestrated irradiating cylinders to avoid circular necrosis and subsequent stenosis. Extensive research is under way to llnd more selective and more stable photosensitizers than HPD and DHE. In the near future, zinc phthalocysnines embedded in liposomes and benzoporphyrin derivative will be used for phase I clinical trials in the U.S.A. and Europe. Prom a clinical point of view, it
NEWS AND VIEWS
125
is clear that, without better dyes than DHE, there is no future for PDT in the upper aero-digestive tract, and in other hollow organs.
2. Conclusions In addition to the common problems encountered with PDT (lack of selectivity of HPD or DHE, skin photosensitivity, problems with accurate tumour depth profiling, etc.), the greatest challenge in treating early pharyngeal carcinomas is the actual impossibility of irradiating the whole lesion homogeneously, except for small lesions located to the pyriform sinuses or to the posterior wall. If the future hope is to apply this treatment modality routinely in oncology, we need to address the following problems: (i) find more selective, more stable photosensitizers with reasonable phototoxicity; (ii) solve the problem of accurately determining the in-depth invasion of early cancers prior to any treatment; (iii) obtain a better knowledge of the patterns of diffusion and absorption of light in different living tissues at different wavelengths; (iv) find light diffusing media (solutions, pastes, etc.) for complex anatomical geometries (pharynx, bronchi) with acceptable light scattering properties and as little loss of transmission as possible. These are great challenges indeed, but they should stimulate alIresearchers from the basic sciences to the clinical applications. Only then can we hopefully see this new treatment modality being widely accepted in the armamentarium against some types of cancers. 1 D. P. Slaughter, H. W. Southwick and W. Smejkal, “Field cancerisation” in oral stratilIed squamous epithelium, Cancer, 6 (1953) 963-968. 2 Ph. Monnier, Le carcinome epidermdide “precoce” de la voie digestive superieure, Th&e de Doctor-at, Lausanne, 1986. 3 T. L. Tio and G. N. J. Qtgat, Atlas of 5’kcmsimstid ultmsonographg, Smith Kline and French, Rijswijk, 1986. 4 Ph. Pasche, Le staging endoscopique du cancer precoce pour la voie digestive superieure, Aktuel. Probl. Otorhinolargngol., 12 (1988) 131-137. 5 Ph. Monnier, M. Savary, Ch. Fontolliet, G. Wagmeres, A. Chatelain, P. Comas, Ch. Depeursinge and H. Van den Bergh, Photodetection and photodynamic therapy of “early” squamous cell carcinomas of the pharynx, oesophagus and trachea-bronchial tree, Lasers Med. Sci., 5 (1990) 149-169.
