Method for treating intraocular diseases

FIELD: medicine, ophthalmology, ophthalmooncology.

SUBSTANCE: one should intravenously inject a photosensitizer photosens at 0.1-1.0 mg/kg patient's body weight. In about 48-72 h since the moment of photosens injection it is important to detect the presence of preparation's therapeutic dosage in the tumor. For this purpose one should specify the coefficient of contrast degree between the tumor and healthy adjacent tissues. Planning of photodynamic therapy should be fulfilled individually by orienting to concrete values of the coefficient of contrast degree in a concrete patient. At the value of coefficient of contrast degree being ≥4, but under 10 it is necessary to irradiate with low single dosages (ranged 80-150 mW/sq. cm) by increasing the number of seances conducted (up to 10). At the value of the above-mentioned coefficient being ≥10.0 irradiation should be carried out once or during 2-3 seances at high single radiation dosages (ranged 150-800 mW/sq. cm). The innovation enables to optimize therapy in patients with intraocular tumors.

EFFECT: higher efficiency of therapy.

2 ex

 

The present invention relates to ophthalmology, namely oftalmologii, and is intended for treatment of intraocular tumors.

According to the statistics of intraocular tumours account for 33.7 percent among tumors of the organ of vision of all localizations, while the share of malignant intraocular tumors reaches 13.2 per cent of the total number of enucleated eyes [Pačes A.I., Brovkin A.F., Zigangirov, Clinical Oncology organ of vision. - Moscow. - Medicine. - 1980 - p.23].

The prior art. Treatment of intraocular tumors are divided into two main types: conservative and liquidation.

To liquidation includes enucleation and Essentiale.

To date, it is proved that the simple removal of tumour of the eye does not solve the problem radically, despite radical resection of the primary tumor site. In the world practice the described cases the development of metastases of malignant melanoma or retinoblastoma after 15-30 years after enucleation [IgA, Century, Likhvantseva "Tumor vascular tract eye - 2001, str-217]. Moreover, comparisons of the frequencies of the 5-year and 10-year survival among patients with uveal melanoma treated with organoboranes methods and liquidation methods (enucleation), indicates a better prognosis and outcomes zabolevaniya case of use of the organ methods [Zimermann LE, I.W. McLean: An evaluation of enucleation of the eye containing a malignant melanoma prevent or accelerate the dissemination of tumour cells? // Br J Ophthalmol. - 1978 - vol.62 - pp.420-427. Zimermann LE, I.W. McLean An evaluation of enucleation in the management of uveal melanomas. // Am J ophthalmol. - 1979 - vol.50 - pp.101-110; Augsburger JJ, Gamel JW, Lauritzen ES. Cobalt-60 plaque radiotherapy versus enucleation for posterior uveal melanoma. // Am J Ophthalmology - 1990 - vol.109 - pp.585-592].

As one of the reasons explaining this phenomenon, the authors who conducted these studies, lead precarious balance between proangiogenic and antiangiogenic factors as in the eye with a tumor, and the patient's body [Zimermann LE, I.W. McLean The Manschot-van Peperzeel concept of the growth and metastasis of uveal melanomas. // Br. J. Ophthalmol. - 1980 - vol.62 - pp.420]. Due to the existence of immune surveillance and the phenomenon of immune privilege in the eye tumor growth over a long period of time (stage T1-3) is constrained. For control of tumor growth in the Arsenal of the immune system many mechanisms. Among them, the secretion of angiogenic factors (e.g., angiostatin,) aimed at neutralization of Pro-angiogenic factors, the secretion of which performs and/or regulates the tumor itself. These Pro-angiogenic factors induce neoangiogenesis in tumors and stimulate its growth. The balance between Pro - and antiangiogenic factors can be saved, if the tumor slowly regresses under the influence of radiation methods of organ preservation treatment. On the background of the slow reduced the I main tumor mass, the level of production of Pro - and antiangiogenic factors gradually fades evenly. However, the situation is totally different when radical removal of the affected eye. Eliminate the tumor - inductor produce angiogenic factors leads to diproduksi Pro-angiogenic factors. This creates favorable conditions for the formation of secondary metastatic sites in those bodies, which were covered with the blood flow to the tumor cells that fall into the systemic circulation at the time of the enucleation. This concept is reflected in other malignant tumors [Weidner N., Carrol P.R., Flaz J. Tumour angiogenesis correlates with metastasis in invasive prostate carcinoma. // Amer. J. Pathol. - 1993 - vol.143, No. 5 - pp.401-409].

Thus, taking into account the above points, it can be argued that organ-sparing treatment of intraocular malignancies preferable to liquidation. Well as well as for benign, since preservation of the eye as organ significantly improves the patient's quality of life.

All ablative treatments are divided into surgical and radiation methods (see table 1)

Table 1
Surgical methodsRadiation methods
Blockstate (synonym: lamellar sclerodermataceae, transscleral local resection)

Andarticle (synonym: retinochoroiditis what I ab interno).
Laser photodestruction,

Brachytherapy,

Proton therapy,

Microwave hyperthermia,

Transscleral thermotherapy,

Transpupillary thermotherapy,

Stereotactic radiosurgery,

Photodynamic therapy

The choice of strategies and method of treatment of a patient with intraocular tumor is determined by the size of the tumor, its localization and/or stage of the cancer process, and also a number of related points. Under related moments we understand the presence of high exudative retinal detachment, secondary hypertension, complicated cataract, hemophthalmos, etc. in Addition, it has the value and presence in the hospital special ophthalmic lasers, suitable for treatment of tumors and/or radioisotope applicators, as well as the level of training of an ophthalmologist and/or professional surgical skills.

Each of these treatment methods has its advantages and disadvantages, as well as their indications and contraindications for their use.

So, laser photodestruction (synonym: laser coagulation) as an independent method of treatment has very limited indications. It is produced when postequalization tumors of small size, when their thickness exceeds 1.5 mm, and the diameter does not exceed before the crystals to 12 mm [Guide oftalmologii. - Ed. Approving. - Moscow. - Medicine - 2002. - str-118]. A prerequisite for its implementation is the absolute transparency of the optical medium and maximum mydriasis, which allows full control during use of the laser.

For coagulation of intraocular tumors used argon (range radiation 488 nm), krypton (range radiation 568-647 nm) and diode lasers (range radiation 810 nm). Exposure to a specified range of light absorption of light energy by the tissue structures of the eye - pigment epithelium of the retina and choroid, with subsequent transformation into heat energy. This causes denaturation of proteins that form the basis of the ability of tumor cells with their subsequent death [ibid]. The mechanism of tumor cell death: coagulation necrosis with subsequent cell-free sclerosis.

The disadvantage of this method is the strict restriction of the size of the tumor. Tumor thickness 1.5 mm cannot destroy [Jaikh AE, Trempe CL, Nasrallah, et al Treatment of small choroidal melanomas with photocoagulation. // Ophthalmic Surg - 1988 - vol.19 - pp.738-742. Lanzetta P; Virgili G; Ferrari E; U. Menchini Diode laser photocoagulation of choroidal I // Int Ophthalmol. - 1995 - vol.96, No. 4 - pp.239-247].

Transcleral brachytherapy is widely used by tumors of the Equatorial and postequalization localization. Indications for brachytherapy determined is carried out also by the size of the tumor [Guide oftalmologii. - Ed. Approving. - Moscow. - Medicine-2002. - str-134]. They are limited in the height of 5 mm and a maximum diameter of 14 mm Juxtapapillary tumors should not promenerat more than 3 mm, the radial size should not exceed 9.5 mm, and the meridional - no more than 1/3 (120°) the circumference of the optic nerve disc. Limitations in size when planning for brachytherapy due to two issues: first, the size and shape of modern applicators, maximally adapted to the size of the eyeball, secondly, the maximum area of exposure to the eye tissue, the excess of which is associated with complications that entail the loss of the eye. The type of applicator also depends on the thickness of the tumor. In the countries of the former USSR using ruthenium and strontium applicators. Abroad successfully used125I and60[Lommatzsch PK. Results after beta-irradiation (106EN/106Rh) of choroidal melanomas: 20 years' experience.//Br J Ophthalmology - 1986 - vol. 70 - pp.844 - 851; Char CH, Castro JR, Quivey JM, et al. Uveal melanoma radiation:125I brachytherapy versus helium irradiation. // Ophthalmology.-1989 - vol.96 - pp.1708-1715; Tjho-Heslinga R.E., J. Davelaar, Kemme H.M. Results of ruthenium irradiation of uveal melanomas: the Dutch experience. // Radiother Oncology. - 1999 - vol.53 No. 2 - pp.l33.137].

The success of treatment is determined by exact calculation of the absorbed dose and not less accurate installation of the applicator over the tumor with overlapping its borders. The applicator is mounted in the zone of localization of the tumor after before kiteley marking its projection on the sclera. Boundary marking melanoma is performed using transpupillary diaphanoscopy on the operating table in terms of anesthesia and maximum drug-induced mydriasis. If it is impossible to define the boundaries of the tumor diaphanoscopy (in cases of amelanotic melanomas) use of Ophthalmoscope control [Manual oftalmologii. - Ed. Approving. - Moscow. - Medicine - 2002. - str-134].

Incomplete regression of the tumor is possible relapses growth or tumor growth under scar [Karlsson UL, Augsburger JJ, Shields JA, et al. Reccurence of posterior uveal melanoma after 60 Co episcleral plaque therapy. // Ophthalmology - 1989 - vol.96 - pp.382-388.]

In the case of relapse growth, incomplete regression, after a year or more earlier (but not earlier than 6 months after the first brachytherapy), possible re-brachytherapy. However, resources and tolerability of the sclera to the re-exposure is very limited. When the total radiation dose to the sclera, approaching 300 Gr, develops scleromalacia where possible organ-preserving treatment is virtually eliminated [Zaruba GD Radiotherapy of tumors of the eye. - Moscow. - 1982 - the Dissertation on competition of a scientific degree of the doctor of medical Sciences - page 343].

According to Russian authors to 60% of irradiated melanoma successfully regress to chorioretinal scar in terms of up to 1.5 years [ibid]. In General, now is th brachytherapy of malignant melanoma is 62.6-87% with stabilization of the disease in 31% of cases, at 5-year follow-up period [Pacher S, Stoller S, Lesser ML, et al. Long-term results of iodine 125 brachytherapy in the management of uveal melanoma. // Ophthalmology. - 1993 - vol.100 - pp.1547 - 1554; Lommatzsch PK. Results after beta-irradiation (106EN/106Rh) of choroidal melanomas: 20 years' experience. // Br J Ophthalmology - 1986 - vol.70 - pp.844-851; Char CH, Castro JR, Quivey JM, et al. Uveal melanoma radiation:125I brachytherapy versus helium irradiation. // Ophthalmology. - 1989 - vol.96 - pp.1708-1715; Tjho-Heslinga R.E., J. Davelaar, Kemme H.M. Results of ruthenium irradiation of uveal melanomas: the Dutch experience. // Radiother Oncology. - 1999 - vol.53 - No. 2, pp.133-137].

The advantage of brachytherapy is the most efficient way compared to coagulation, the absence of risk for the development of local dissemination, non-invasive. Under the noninvasive we understand in this particular case, the safety of the sclera of the affected eye. To install the applicator does not require special surgical skills and sophisticated equipment.

The disadvantages include strict limitations on the size of the tumor, the restriction on the multiplicity of the use of the method, long duration rehabilitation, high likelihood of postradiation complications.

Complicated brachytherapy depending on the time of development can be divided into early and late. In addition, depending on the capabilities of carabellese, they are classified as reversible and irreversible. The early complications are iridotsiklity, increased intraocular pressure, exudative itslockedstate, detachment of the choroid, partial hemophthalmus. These States are avoided by using drug therapy. The use of anti-hypertensive Mydriatics, anti-inflammatory drugs can cope in most cases [Guide oftalmologii. - Ed. Approving. - Moscow. -Medicine - 2002. - str-134].

Optic neuropathy with optic atrophy develops in 44% of patients with juxtapapillary melanoma [Archer D, Gardiner T. Ionizing radiation and the retina. // Curr Opin Ophthalmol. - 1994. - Vol.5. - P.59-65]. Ischemia of the retina, resulting in neovascular glaucoma may develop after 1.5 years after brachytherapy in the background fully regressed tumors with extensive areas irradiation of tumors prequaternary and Equatorial localization [Kim MK, Char DH, Castro JL, et al. Neovascular glaucoma after helium ion irradiation for uveal melanoma. // Ophthalmology. - 1986. - Vol.93. - P.189-193]. This state is not stopped by normal antiglaucoma preparations and usually ends with enucleation after numerous attempts to resolve the hypertension. Short-term effect can be achieved using reapplication ciliary body [ibid].

Radiation cataract develops in a more long-term follow up [Seddon JM, Gragoudas ES, Egan KM, et al. Uveal melanomas near the optic disc or fovea, visual results after irradiation. // Ophthalmology. - 1987. - Vol.94. - P.354-361; Madreperia SA; Hungerford JL; Plowman PN. Choroidal hemangiomas: visual and anatomic esults of treatment by photocoagulation or radiation therapy. // Ophthalmology. - 1997 - vol.104, No. 11 - pp.1773-1778; discussion - p.1779].

At high radiation doses on the surface of the sclera possible radiation necrosis with subsequent development of defects in the sclera, which shall be borne by the donor sclera.

Proton therapy (synonym narrow proton medical beam-UMP) represents one type of radiation treatment that allows due to the small dispersion of the energy beam and a specific mileage in the tissues to form the dose field, adequate volume tumors with a high dose gradient at the border of the tumor. The biological effect of such exposure is targeted destruction of tumor tissue in the most sparing irradiation of healthy structures of the eye. Proton therapy is carried out in cases where other radiation methods can not give a positive effect [Guide oftalmologii. - Ed. Approving. - Moscow. - Medicine - 2002. - str-138].

The analysis of the vast experience gained in the Department of oftalmologii and radiology IRI eye diseases, Helmholtz Zentrum, allows the authors to consider this method an alternative to enucleation and essentialy orbit [ibid]. According to their data, manage to keep eyes as cosmetic body in 75% of patients, and preserve visual function - 50%. In 5% of cases the tumor is a recurrence of the growth [ibid].

Efficiency UMPP when PLN is quality melanomas of the choroid is quite high. Thus, according to E.S.Gradoudas full local control was achieved in 62% of cases. Local recurrence was diagnosed in 45 people, with 14 patients eye was angleiron in connection with suspected recurrence of growth, which, however, was not confirmed histologically. Relapses occurred in the interval between 5,2 months and 10.5 years after exposure. Overall recurrence rate was 3.0% and 4.2% at 5 and 10-year periods of observation. In 22 cases, the cause of relapse was incomplete capture the edge of the tumor in the radiation zone, 23 - extrascleral out of the tumor (8), anulara melanoma (6) and the radiation resistance of tumor (9 people) [Gradoudas E.S. et al. Long therm risk of local failure after proton therapy choroidal. - // Ophthalm Surg. - 1987 - vol.98 - pp.383-389].

Thus, despite the wider possibilities of the method compared with brachytherapy, WMP also has a number of shortcomings in the complexity of planning and developing a wide range postradiation complications.

So, when injected into the radiation zone of the cornea may develop keratitis and/or postradiation keratopathy, which clinically manifests itself in the form of point subepithelial and stromal infiltrates and has a sluggish current flow. In the long term can develop radiation cataract or progress is complicated sectoral cataract. Irradiation of large areas (with large tumor size) spragens the development of neuro - and retinopathy [Lumbroso L, Desjardins L, Levy C, et al. Intraocular inflammation after proton beam irradiation for uveal melanoma. // Br J Ophthalmol. - 2001. - Vol.85. - P.1305-1308] Munzenrider JE. Proton therapy for uveal melanomas and other eye lesions. // Strahlenther-Onkol. - 1999 - vol.175 - Suppi 2 - pp.68-73;

Seddon J, Gradoudas ES. Albert D. Ciliary Body and choroidal melanomas treated by Proton beam irradiation. // Arch Ophthalmol - 1983 - vol.101 - pp.1402 - 1412.].

The most common complication of proton therapy - secondary glaucoma, the reason of which is imbibery the angle of the anterior chamber and schlemm's canal pigment toxins, tissue detritus and their toxic products of decomposition, followed by lysis of trabeculae [Lee V; Hungerford JL Proton beam therapy for posterior pole circumscribed choroidal haemangioma. // Eye. - 1998 - vol.12 No. 6 - pp.925-928; Ritland JS; Eide N; Tausjo J. External beam irradiation therapy for choroidal haemangiomas. Visual and anatomical results after a dose of 20 to 25 Gy.// Acta Ophthalmol Scand. - 2001 - vol.79, No. 2 - pp.184-186].

Thermotherapy is one of the modern radiation treatment of intraocular tumors. The effect of thermotherapy based on a combination of volumetric hyperthermia of the tumor from 45 to 65° and coagulation intratumoral vessels. Thermotherapy is of two kinds-transpupillary and transcleral.

Transpupillary thermotherapy (TTT) is performed using diode lasers of different models (for example, OcuLight SLx, IRIS Medical instruments. Inc.) with the length of volny 810 nm. The power of radiation exposure (360-1000 mW and a beam diameter of 1.5-3-10 mm) varies depending on the degree of pigmentation and size of the tumor. Expo is ice irradiation ranges from 30 to 90 seconds [D.M. Robertson Buettner H., Transpupillary thermotherapy as primary treatment for small choroidal melanomas. // Trans Am Ophthalmol. Soc. - 1999 - vol.97 - pp.407-434.]. When the directional effect of the diode laser the specified parameters within 60 seconds, the temperature in the zone of influence is increased up to 45-65° [Journee-de-Korver HG, Verburg-van der Marel EH, oosterhuis on JA, et al. Tumoricidal effect of hyperthermia by near infrared irradiation on pigmented hamster melanoma. // Lasers Light Ophthalmol. - 1992. - Vol.4. - P.175-180. Oosterhuis on JA, Journee-de-Korver HG, Kakebeeke-Kemme NM, BleekerJC. Transpupillary thermotherapy in choroidal melanoma. // Arch Ophthalmol. - 1995. - Vol.13. - P.315-321].

The initial indication for TTT served tumor thickness up to 5 mm, located in the posterior pole of the eye. In 30% of cases, a complete regression of the tumor (up to 3 mm) occurs within 3 months. Incomplete regression of therapy can be repeated to obtain a flat chorioretinal scar. In some cases, the regression of tumors in a single session TTT can last a whole year of observation [ibid]. The 13.3-18% of the tumor may be resistant to this method of treatment, as well as to any other radiotherapy, including brachytherapy [oosterhuis on JA, Joumee de Korver HG, Kakebeeke Kemme NM, et al. Transpupillary thermotherapy in choroidal melanomas.// Arch Ophthalmology. - 1995 - vol.113 - pp.315-321].

Transpupillary thermotherapy can be used as an independent method of treatment or in combination with transscleral brachytherapy. This combination is applied in cases when prominence about what whole exceeds 5 mm [ibid]. The sequence of application of these methods may vary. Sometimes they can be applied simultaneously. For example, M Starzycka first by external radiation therapy106Ru or125J applicators, but with little effect adds TTT. Some authors have used quite successfully this combination when the tumors reached a height of 10 mm, While the reduction of melanoma up to 30% of the original volume achieved in 77.8% of treated tumors [Schneider H., Fischer, K., Fietkau R.F., R.F. Guthoff Transpupillare Thermotherapie des malignen Aderhautmelanoms. Erste First Experiences. // Ophthalmologe. - 1998 - vol.95, No. 11 - pp.765-770.]. 10-18,3% of melanomas, according to various authors, are resistant both methods [ibid]. And in 25% of cases there is a recurrence of melanoma growth smallest size up to 3 mm after a single TTT during the observation period up to 15 months. Many authors indicate that the most likely to relapse growth juxtapapillary melanoma [ibid].

The effectiveness of TTT is quite high. Thus, according to J. K. Shields, 94% of tumors (diameter of 7 mm and a thickness of 2.8 mm) completely regress. 2% of cases require repeated sessions TTT. 6% of cases are resistant not only to TTT, but also to brachytherapy and end with enucleation. Visual functions remain at the same level or improved in 58%, worse in 42%. The reduction of visual function due to macular tumor localization, soudi is the obstruction or secondary postradiation semiseria [Shields J.A., Shields C.L, De Potter P, et al. Transpupillary thermotherapy in the management ofchoroidal melanoma. // Eye. - 1997-vol.1 - pp.676-679.].

Thus, the advantages of the TTT should include non-invasive, relatively high efficiency, the possibility of holding sessions of exposure in the outpatient setting, the possibility of a replay session, the preservation of visual function.

Disadvantages can be considered incomplete regression in some cases, a high frequency of recurrence of tumor growth, development of radiation resistance and the number of postradiation complications.

Among the complications that can occur after TTT, allocate subretinal the choroidal neovascularization (6-13,8%), partial hemophthalmus (3.4%), local tractional retinal detachment (in 20% of cases), retinal detachment caused by errors made during TTT (perforation of the retina in the macular region, 1%), exudative neurosensory detachment, Vitrea [Balestrazzi, A., Blasi M.A. Retinal detachment due to macular hole after transpupillary thermotherapy ofchoroidal melanoma. // Retina. - 2001 - vol.21 - No.4 - pp.384-385], occlusion of the Central retinal vessels (20,6%), leading to loss of Central vision [Currie Z.I., Rennie I.G. Retinal vascular changes associated with transpupillary thermotherapy for choroidal melanomas. // Retina - 2000 - vol.20 No. 6 - pp.620-626.].

Shields indicates that the risk of retinal traction is greatly increased when tumors extending from the macula in the temporal direction [J.A. Shields, Shields C.L, De Potter P, et al. Transpupillary thermotheray in management of choroidal melanoma. // Eye - 1997 - vol.1 - pp.676-679]. TTT juxtapapillary melanomas is associated with a high risk of developing retinal neovascularization due to obstruction of the large retinal vascular arcades, is caused by exposure to radiation energy [ibid]. Kiratli leads as one of the complications TTT pigment dispersion in the vitreous body [Kiratli h, Bilgic S. Cal P. Intravitreal pigment dispersion as a complication of transpupillary thermotherapy of choroidal melanoma. // Retina. - 2000 - vol.20 No. 4 - pp.408-409]. Other authors indicate that multiple tumors TTT lead to calcification [Mosci C; Polizzi A, Zingirian m Transpupillary thermotherapy for circumscribed choroidal hemangiomas: first choice in therapy. // Eur J Ophthalmol. - 2001-vol.11, No. 3 pp.316-318.

Infrared TTT. It is known that the effectiveness of TTT densely pigmented tumors better than when amelanotic tumors of the choroid. In the literature there are pointing to the possibility of strengthening the effectiveness of TTT thanks to the use of contrast - indocyanine green. Contrast is injected intravenously for 50-60 minutes until TTT [Kamal A; Watts AR; Rennie IG. Indocyanine green enhanced transpupillary thermotherapy of circumscribed choroidal haemangioma.// Eye. - 2000 - vol.14 No. 5 - pp.701-705 Joumee-de Korver H., de Boer A.G. Infrared thermotherapy of amelanotic tumors. Abstract book of the International Congress of Ocular Oncology. - Amsterdam, the Netherlands, the - 2001 - pp.124]. Adjuvant potential of indocyanine green proved histomorphologically: increases the area and depth of necrosis induced by TTT.

Along with TTT, increasingly in ofta is monologue use transscleral thermotherapy (TST) using the same type of laser radiation, as in TTT. Irradiation is carried out using a special fiber that result in direct contact with the sclera, in the projection of the base of the tumor. Pre-mark the borders of the tumor on the sclera, by transillumination eyeball from the opposite side through the sclera or through the pupil.

The sclera makes the irradiation power up to 2500 mW, followed by heating the surface of the sclera to a temperature of 44.5°and the temperature at the boundary of the tumor-sclera up to 60°C. While necrosis was covered up to 5 mm tumor thickness [Keunen J.E.E., oosterhuis on, Rem, A.I., Joumee-de Korver H. Transcleral thermotherapy in choroidal melanoma: first results. // Abstract book of the International Congress of Ocular Oncology. - Amsterdam, the Netherlands, the - 2001 - pp.107]. Preliminary experimental data showed that the sclera maintains temperature exposure up to 60°C for 10 minutes without structural changes [ibid].

Attempts ophthalmooncologic to find a more effective combination among organ-sparing treatment suggests that the problem is far from being resolved.

At the turn of XX-XXI centuries appeared and began to actively implemented a new method, called photodynamic therapy (PDT) of intraocular tumors. The essence of the method lies in the fact that the patient is injected photosensitizer (PS), which in a certain timeframe (they each FS) selectively nakaplivalos is in the tumor, this creates a gradient contrast between the concentration of the drug in the pathological lesion and the surrounding healthy tissues of the eye. This allows you to focus the irradiation exclusively in the tumor. Irradiated by the laser action on the wavelength in the maximum of the absorption spectrum of the used photosensitizer. Develops a cascade of photodynamic reactions, the main biological effect of which is destruction of the tumor. At the same time as photosensitizers can be used in a variety of natural and synthetic dyes [ed. Evangelos S. Gradoudas et al. Photodynamic therapy of ocular diseases. - Lippincott Williams Wilkins - USA - 2004 - p.272]. Irradiation is carried out traditionally transpupillary, that is, through the most advanced pupil.

The method is tested and has been used abroad in the treatment of a number of intraocular tumors.

The best results are associated with little pigmented tumors, which include amelanotic melanoma, osteomas and hemangioma of the choroid [Jurklies, Anastassiou G, S Ortmans, et al. "Photodynamic therapy using verteporfin in circumscribed choroidal haemangioma" // Br J of Ophthalmology - 2003 - Vol.87 - P.84-89; Madreperla SA. "Choroidal I treated with photodynamic therapy using verteporfin." // Arch Ophthalmol. - 2001. - Vol.119, No. 11 - P.1606-1610; Porrini G. A. Giovannini et al // Photodynamic therapy of circumscribed choroidal approach. //Ophthalmology. - 2003. - Vol.110. - P.674-680; Battaglia Parodi M, Da Pozzo S, et al. Photodynamic therapy for choroidal neovascularization associated with choroidal osteoma.// Retina. - 2001. - Vol.21. - P.660-711].

Moreover, if a contraindication for use of brachytherapy or thermotherapy in hemangioma of the choroid is a serous retinal detachment, photodynamic therapy of such tumors proceeds favorably [Robertson DM. // Photodynamic therapy for choroidal approach associated with serous retinal detachment. Arch Ophthalmol. - 2002. - Vol.120. -P.1155-1161].

In another paper the authors also indicate that during PDT, along with complete regression of hemangiomas, there is resorption of subretinal exudate. The effect lasted up to 18 months. As FS, the authors used Vicodin, based on the calculation of the dose of 6 mg / m2the surface of the body. The drug was administered intravenously. Irradiated on the laser model Visulas 6905 (Carl Zeiss-Meditech AG, Jeud Germany) with a wavelength of 689. For tumors greater than 2 mm in thickness, light dose radiation exposure was 100 j/cm2and the duration of the session - 186 sec, while tumors up to 2 mm, respectively - 75 j/cm2and 125 seconds. [Porrini G, Giovannini A, Amato G, loni A, Pantanetti M. // Photodynamic therapy of circumscribed choroidal approach. // Ophthalmology. - 2003. - Vol.110. - P.674-680.].

As you can see from the presented data, the method is certainly effective, even in cases where brachytherapy or therapy cannot be used. The method has a number of indisputable advantages:

first, it is non-invasive,

secondly, radiation sessions when geoeffective may be repeated

thirdly, PDT can be carried out in the am is ulatory conditions, what is more comfortable for the patient.

However, the method is not without disadvantages. According to foreign colleagues, the method has limited capacity. Revealed some regularities. So it is established that the more pigmented tumor, the worse the efficiency and lower the depth of penetration into the tumor tissue, and therefore, a possible partial destruction of the tumor [Kim RY, Nor LK, Foster BS, et al. Photodynamic therapy ofpigmented choroidal melanomas of greater than 3-mm thickness. // Ophthalmology. - 1996. - Vol.103. - P.2029-2036. Gonzalez VH, Nor LK, Theodossiadis PC, et al. Photodynamic therapy of pigmented choroidal melanomas. // Invest Ophthalmol Vis Sci. - 1995. - Vol.36. - P.871-878]. A partial effect in the future is associated with recurrence of tumor growth, and, hence, with repeated courses of PDT.

In addition to these shortcomings, serious disadvantages of PDT with foreign photosensitizers (e.g., Visudyne) include a wide range of complications which can be classified as General or system and special ophthalmologic or local.

Among the local complications of PDT identified chemosis, iritis, cataract, Vitrea, detachment of the retina and choroid [Barr H, Kendall C, Reyes-Goddard J, Stone N. Clinical aspects of photodynamic therapy. // Sci Prog. - 2002. - Vol.85. - P.131-150; Holz, T. Exudative Complications After Photodynamic Therapy. // Arch Ophthalmol. - 2003. - Vol.121. - P.1649-1652].

Among the systemic effects observed cutaneous photosensitivity [Barbazetto IA, Lee TC, Rollins IS et al. Treatment of choroidal melanoma using photodynamic therapy. // Am. J Ophhalmol. - 2003. - Vol.135. - 898-899].

Meanwhile, on the domestic pharmaceutical market, a domestic photosensitizers. We have assumed that they can potentially be applied in ophthalmology in General and in oftalmologii in particular. Among them photosense - derived phthalocyaninato series. The effectiveness of this drug proved photodynamic therapy of many cancers [Site: http://www.magicray.ru/RU/lecture/L1/1.html.].

Our preliminary experimental studies have revealed the prospects of their application in oftalmologicheskiy problems.

The closest analogue of the present invention is a method of treatment of intraocular tumors, including photodynamic therapy with Visudyne as a photosensitizer [Jurklies, Anastassiou G, S Ortmans, et al. "Photodynamic therapy using verteporfin in circumscribed choroidal haemangioma" // Br J of Ophthalmology. - 2003 - Vol.87 - P.84-89].

The task of the invention is to develop a highly effective method for the treatment of intraocular tumors, which by its effectiveness is superior to the efficiency of the method, we have taken the closest analogue, however, deprived of all his faults.

The technical result of the invention is the complete destruction of any intraocular tumors.

The technical result is achieved due to the use of certain doses of photosensitizer Photosense, and by p the th individual planning mode laser exposure depending on the values of concentrations of photosense in tumor tissue healthy.

Our proposed method consists in pre-intravenously to patients with intraocular tumors photosensitizer Photosense from the calculation of doses from 0.1 to 1 mg/kg of patient's weight and the subsequent conduct of photodynamic therapy with the value of the contrast ratio (represents the ratio of drug concentration in the tumor concentration in normal surrounding tissues), which is assessed within 3 days. While PDT is performed on the laser with a wavelength of 675 nm with a total radiation power from 80 to 800 mW/cm2with the help of special fundus lenses Minster.

The minimum dose of injected photosense was determined we empirically in experiments on animal models of intraocular tumors on contrast ratio. The contrast ratio was not reached with 4.0 a dose of Photosense below 0.1 mg/kg And at a dose of Photosense above 1.0 mg/kg weight of the patient began to develop skin toxicity. These data formed the basis of a fixed range of therapeutic doses of Photosense.

Also it was empirically established that only the contrast ratio allows for strictly dosed radiation, selectively directed the pathological focus in the eye. When this principle is used the most gentle attributed the I to functionally intact tissues of the eye. To achieve efficiency, the contrast ratio should not fall for the mark 4. The specified contrast ratio evolved in time from 48 hours to 72 hours after the introduction of Photosense.

So, by the irradiation start after clarification of the contrast ratio. It is defined using a special spectroscopic complex LESA-01 - "BIOSPEC".

We have found that a high contrast ratio (>10) allows you to give all of the total radiation dose simultaneously without much risk of damage to surrounding healthy tissues of the eye - the retina and choroid. Low contrast ratio require a different approach: repeated sessions of exposure in small doses. This approach allows us to avoid complications such as edema and photothrombosis main retinal vessels, edema and exudative detachment of the retina and the choroid, which develop during PDT with Visudyne.

The dose of injected photosense as the exposure dose is determined by the size of intraocular tumors. The larger the tumor, the higher dose of photosense and laser exposure. The destruction of a large tumor of the array requires the use of large doses of photosensitizer and large cumulative radiation doses. As mentioned above, preliminary experimental data showed that coefficie the t contrast in intraocular tumors reached a level of 4.0 at a dose of Photosense below 0.1 mg/kg (or rather 2,0). And at a dose of Photosense above 1.0 mg/kg of body weight developed skin toxicity. These data were transferred to the clinic.

Irradiation is carried out traditionally transpupillary, that is, through the pupil, focusing the laser light on the pathological focus using the lens Minster, which is placed on the patient the patient's eye.

Thus, our proposed method PDT intraocular tumors, as well as the way that we took for the nearest equivalent, consists of prior intravenous administration of a photosensitizer followed by transpupillary laser exposure. But our method differs substantially from its counterpart, namely, first, that as a photosensitizer, we propose to apply the photosense instead of Visudyne.

Secondly, we propose to perform PDT amid maximum of the gradient of the contrast, which is detected by analyzing the spectra accumulation of the drug. To do this within the first 3 days spend clarification of the contrast ratio of the accumulation of Photosense in the pathological focus.

Thirdly, we offer during PDT and planning of radiation treatment to focus on refined during diagnostic contrast ratio. In terms of contrast ratio, close to a 4.0, but less than 10, the total planned radiation dose SL is blowing be divided into several sessions (10 sessions) PDT, the radiation of conduct small single doses (80 to 150 mW/cm2). When the contrast ratio >10.0 irradiation can be performed once or for 1-3 sessions with large single dose of radiation doses from 150 to 800 mW/cm2).

PDT is performed on laser facility with a wavelength of 675 nm (the maximum of the absorption spectrum of Photosense).

The advantages of our proposed method, in our opinion, is the selectivity or strictly targeted delivery of radiation exposure in tumor tissue, representing the depot photosense. This allows you to minimize postradiation complications of PDT as chemosis, iritis, cataract, vitreitis, detachment of the retina and the choroid.

We have implemented our invention in practice, and has received confirmation of eligibility and simplicity in technical execution.

The method is as follows.

At the first stage of intravenously injected photosensitizer photosense based doses of 0.1-1.0 mg/kg weight of the patient.

After 48 hours of intravenous Photosense, specify the contrast ratio between the tumor and the surrounding healthy tissues of the eye using a special spectroscopic complex LESA-01 - "BIOSPEC".

When reaching into the pathological focus therapeutic doses (at which the contrast ratio ≥4,0) are individually the scheduling mode of radiation exposure. Thus, when the contrast ratio ≥4 but less than 10, irradiated small single doses (80 to 150 mW/cm2), increasing the number of sessions (up to 10).

In the case of a high contrast ratio may 1-3-fold irradiation with large single doses (150 to 800 mW/cm2).

Radiation effects in photodynamic therapy of intraocular tumors carry out transpupillary using fundus lens Minster spot light from 600 to 10 mm laser with a wavelength of 670 nm in the conditions of maximum mydriasis.

Example 1. Patient S., aged 65. Diagnosis: juxtapapillary melanoma of the choroid (.T2N0M0) of the right eye. On the left eye of primary senile cataract. The original size of the tumor height was 3.0 mm, diameter 7 mm

The patient entered the photosense the rate of 0.3 mg/kg of body weight. After 48 hours have been spent determining the contrast ratio. The index reached a maximum (=12) after 72 hours. PDT spent transpupillary on the background of this peak laser radiation at a wavelength of 675 nm, the radiation dose was 250 mW/cm2the number of PDT sessions reached 3, and the total dose PDT=750 mW/cm2. When selecting a single radiation dose is focused on the experimental data: at higher dose to the tumor such height has developed edema and exudative retinal detachment and with less effect was insufficient. The diameter of the light spot is the focal plane radiation exposure was 10.0 mm The tumor was irradiated uniformly, capturing around 1.5 mm healthy surrounding tissue in order to avoid the hidden growth.

After 1 month there was a regression of the tumor size reduction to 1.0 mm in height. After 3 months on the former site of the tumor formed flat chorioretinal scar.

Example 2. The patient 46 years. The diagnosis of hemangioma of the choroid of the left eye. Tumor size 2.5 mm in height and 10 mm in diameter. The patient entered the photosense the rate of 0.2 mg/kg of body weight. After 48 hours from the moment of introduction of said contrast ratio. He was equal to 5. PDT was performed transpupillary laser radiation at a wavelength of 675 nm, small single doses of 150 mW/cm2in order to avoid complications, bringing the total radiation dose of up to 750 mW/cm2for 5 sessions. Sessions were repeated every 2-3 days as decreased swelling of the tumor and surrounding tissue and newly developed contrast ratio. After 2 months the patient fully regressed hemangioma.

All patients treated under the proposed method, developed positive clinical effect in the form of full or partial regression of the tumor. Complications are not checked.

Thus, we proposed a method for the treatment of intraocular tumors is an effective treatment method.

A method for the treatment of intraocular tumors, consisting in the provedenii photodynamic therapy by intravenous injection of photosensitizer dose of 0.1-1.0 mg/kg of body weight and transpupillary exposure to laser radiation at a wavelength of 675 nm, when irradiation is carried out within 48-72 h after injection of the drug, determine the contrast ratio and the ratio the contrast ratio of from 4 to 10 exposure dose is 80-150 mW/cm2and the multiplicity of radiation sessions range from 3 to 10, and when the ratio of contrast ratio higher than 10, the exposure dose is 150-800 mW/cm2and the number of sessions 1-3.



 

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29 cl, 12 ex, 2 tbl

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7 cl, 3 tbl, 17 ex

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1 cl, 3 ex, 1 tbl

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1 ex

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3 ex

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3 dwg, 13 ex, 2 tbl

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1 ex

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