RU2452444C1 - Method of organ-preserving treatment of intraocular tumours - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: claimed invention relates to ophthalmology, namely to ophthalmic oncology and is intended for organ-preserving treatment of intraocular tumours. Transpupillary PDT is performed. After 3-20 days treansscleral PDT is carried out. After tumour devitalisation, total vitrectomy and endoresection of tumour is performed. Vitreous cavity is filled with substitute of vitreous body and laser coagulation of retina is carried out.

EFFECT: method ensures radical complete destruction of tumour with extension of indications to organ-preserving treatment with recovery of functional reserves of eye.

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Description

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

Among eye organ tumors, intraocular tumors take the second place, second only to neoplasms of the eyelids in frequency. Among intraocular tumors, tumors of the retina and neoplasms of the vascular tract of the eye are distinguished. They are found at almost any age. In childhood, retinal tumors prevail. They are mainly represented by retinoblastomas. The lion's share of adult tumors are neoplasms of the vascular tract of neuroectodermal origin (pigmented and non-pigmented nevi and melanomas). A smaller part of them has mesodermal origin (hemangiomas) [Paches A.I., Brovkina A.F., Ziangirova G.G. Clinical oncology of the organ of vision. - Moscow. - The medicine. - 1980 - p. 23].

The level of technology.

Treatment of intraocular tumors is divided into two main types: organ-preserving and elimination.

For almost 4 centuries, enucleation remained the only and no alternative treatment for all intraocular tumors. However, over the past half century, thanks to the achievements of radiation medicine in the arsenal of ophthalmologists, new technologies have appeared that allow not only to destroy the tumor, but also to save the eye as an organ. Today, among these technologies, preference is given to those organ-preserving methods that have a selective effect and, therefore, are less traumatic for functionally significant eye structures that are not involved in the neoplastic process. It is these methods that are more promising for visual functions.

Today, radiation treatment methods are most popular among organ-preserving types of treatment: brachytherapy, laser photodestruction, thermotherapy, photodynamic therapy using photosensitizers.

Each of the above treatment methods has its advantages and disadvantages, as, however, its indications and contraindications to their use.

Laser photodestruction (synonym: laser coagulation) as an independent method of treatment has very limited indications. It is performed for small-sized post-equatorial tumors, when their thickness does not exceed 1.5 mm, and the diameter does not go beyond 12 mm [Ophthalmic Oncology Manual. - ed. A.F. Brovkina. - Moscow. - The medicine. - 2002. - p. 116-118]. A prerequisite for its implementation is the absolute transparency of optical media and maximum mydriasis, which allows full control during the procedure of azure photodestruction.

For laser photodestruction of intraocular tumors, argon (radiation range 488 nm) and krypton (radiation range 568-647 nm) are used. Under the influence of the indicated emission spectrum, light energy is absorbed by the tissue structures of the eye - the retinal pigment epithelium and choroid, followed by its conversion into thermal energy. This type of exposure causes the denaturation of proteins, which form the basis of the activity of tumor cells with their subsequent death [ibid.]. The mechanism of tumor cell death: coagulation necrosis followed by cell-free sclerosis.

The disadvantages of the method are its limited capabilities: it is not indicated for tumors thicker than 1.5 mm. The radiation penetrating power in the indicated spectral wavelength range is not high. In addition, exposure in this mode is accompanied by the formation of a dense coagulation film, which prevents further penetration of laser beams. [Jalkh 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; Menchini U. Diode laser photocoagulation of choroidal hemangioma // Int Ophthalmol. - 1995 .-- vol. 96. - No. 4. - pp. 239-247].

Transcleral brachytherapy is one of the common methods for treating intraocular tumors. It is widely used in tumors of equatorial and post-equatorial localization. The method is based on a short distant (contact) effect on the base of the tumor from the sclera of various radioactive radiation sources. The radionuclides are placed on a matrix located in a special sealed stainless steel container, having the shape of a spherical segment 1 mm thick. This design is called an ophthalmic applicator. The ophthalmic applicator is placed on the sclera (on the site of the projection of the base of the tumor on the sclera), fixing it for special arches with interrupted sutures.

Indications for brachytherapy are determined by the size of the tumor [Ophthalmic oncology manual. - ed. A.F. Brovkina. - Moscow. - The medicine. - 2002. - p. 124-134]. They are limited to a height of 5 mm and a maximum diameter of 14 mm. Juxtapapillary tumors should not be more than 3 mm prominence, their radial size should not exceed 9.5 mm, and their meridional size should not exceed 1/3 (120 °) of the circumference of the optic disc. Limitations in size when planning brachytherapy are due to two points: firstly, the size and shape of modern applicators, the most adapted to the size of the eyeball, and secondly, the maximum allowable area of irradiation of eye tissue, the excess of which is associated with complications that entail eye death. The type of applicator also depends on the thickness of the tumor.

With incomplete tumor regression, recurrence of growth or growth of the tumor from under the scar is possible [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].

Moreover, in the case of growth recurrence, or with incomplete regression, after a year or a little earlier (but not earlier than 6 months from the moment of the first brachytherapy), repeated brachytherapy is possible. However, the resources and tolerance of the sclera to repeated irradiation are very limited. With a total radiation dose to the sclera approaching 300 Gy, scleromalacia develops, in which the possibilities of organ-preserving treatment are practically eliminated [Zarubei G.D. Radiotherapy of eye tumors. - Moscow. - 1982 - Thesis for the degree of Doctor of Medical Sciences. - 343 p.].

The disadvantages include: strict restriction on the size of the tumor, restriction on the frequency of use of the method, a long duration of rehabilitation and a wide range of these complications with a high probability of their development.

Thermotherapy is another radiation method for treating intraocular tumors, where infrared radiation from a diode laser at a wavelength of 810 nm is used as a radiation source. The effect of thermotherapy is based on a combination of volumetric hyperthermia of a tumor from 45 to 65 ° and coagulation of intratumoral vessels. Thermotherapy is of two types - transpupillary and transscleral.

The advantages of TTT include: non-invasiveness, relatively high efficiency, the possibility of conducting irradiation sessions on an outpatient basis, the possibility of repeating the sessions, maintaining visual functions.

The disadvantages are: incomplete regression in a number of cases, a high rate of relapse of tumor growth, the possibility of developing radiation resistance and a number of post-radiation complications.

Recently, there has been a tendency to combine several methods. So, transscleral thermotherapy can be combined with TTT.

Many authors use a combination of TTT with brachytherapy (the so-called sandwich method) [Seregard S., Landau I. Transpupillary Thermotherapy as an adjunct to rutenium plaque radiotherapy for choroidal melanoma. // Acta Ophthalmol. Scand. - 2001 .-- vol. 79. - No. 1. - pp. 19-22; Keunen J.E., Journee de Korver. J.G. Transpupillary thermotherapy of choroidal melanoma with or without brachytherapy: a dilemma. // Br J Ophthalmology - 199 - vol. 83 - No. 8 - pp. 987-988].

Attempts by ophthalmic oncologists to find more effective combinations among organ-preserving treatment methods indicate that the problem is far from being resolved.

At the turn of the XX-XXI centuries, a new method appeared in their arsenal and began to be actively introduced, called photodynamic therapy (PDT) of intraocular tumors. The essence of the method lies in the fact that the patient is injected with a photosensitizer (PS), which at certain times (they are different for each PS) selectively accumulates in the tumor, while a certain contrast coefficient is created between the concentration of the drug in the pathological focus and the surrounding healthy eye tissues. The difference in the concentration of the drug in the pathological focus and surrounding normal tissue allows you to focus the effect exclusively in the tumor. They are irradiated with a transpupillary laser action at a wavelength at the maximum of the absorption spectrum of the photosensitizer used. A cascade of photodynamic reactions develops, the main biological effect of which is the destruction of the tumor. At the same time, various natural and synthetic dyes can be used as photosensitizers. Irradiation is carried out traditionally transpupillary, that is, through the most dilated pupil.

The method has been tested and found application abroad in the treatment of intraocular tumors. The best results are associated with poorly pigmented tumors, which include non-pigmented melanomas, osteomas and hemorrhages of the choroid [B Jurklies, G Anastassiou, 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 hemangioma treated with photodynamic therapy using verteporfin" // Arch Ophthalmol. - 2001. - Vol.119 - N 11 - P.1606-1610; Porrini G, Giovannini A, et al // Photodynamic therapy of circumscribed choroidal hemangioma. // 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].

The method has a number of indisputable advantages:

Firstly, it is non-invasive.

Secondly, exposure sessions with hypoeffect can be repeated.

Thirdly, PDT can be performed on an outpatient basis, which is more comfortable for the patient.

The method has some limited features. Some patterns were identified. So, it was found that the more pigmented the tumor, the worse the efficiency and the less depth of penetration into the tumor tissue, and therefore, incomplete destruction of the tumor is possible [Kim RY, Hu LK, Foster BS, et al. Photodynamic therapy of pigmented choroidal melanomas of greater than 3-mm thickness. // Ophthalmology. - 1996. - Vol. 103. - P.2029-2036. Gonzalez VH, Hu LK, Theodossiadis PC, et al. Photodynamic therapy of pigmented choroidal melanomas. // Invest Ophthalmol Vis Sci. - 1995. - Vol. 36. - P.871-878]. An incomplete effect in the future is associated with relapse of tumor growth, and therefore with repeated courses of PDT.

Meanwhile, domestic photosensitizers appeared on the domestic pharmacological market in the arsenal of oncologists. We suggested that they could potentially be used in ophthalmology in general, and in ophthalmology, in particular. Among them, photosens is a derivative of the phthalocyanine series, as well as plant photosensitizers - chlorins. The effectiveness of these drugs has been proven in PDT of many oncological diseases [Site: http://www.magicray.ru/RU/lecture/L1/1.html].

Our preliminary clinical and experimental studies have revealed the promise of their use in ophthalmic oncological problems.

We also found that one of the ways to increase the efficiency of PDT can be the transsclerical approach for laser irradiation (RU 2290905, 2007). This method is taken as the closest analogue. The fact is that tumors developing in the choroid initially have a pronounced supply or supply network of vessels located at the base. Exposure through the pupil has only a partial effect. It is more advisable to deprive her of nutrition, causing photothrombosis of the supplying major vessels, and thus cause tumor necrosis.

We have developed a method of organ-preserving treatment, which is based on the devitalization of tumor cells with the help of PDT, carried out both by transpupillary and transscleral methods, followed by endoresection of a non-viable tumor from the vitreous cavity.

The use of two accesses in the “sandwich method” mode (from the pupil + from the sclera) increases the therapeutic effect and is accompanied by a more complete destruction of the tumor. It is known that tumors of the choroid have double blood supply from the vessels of the retina and vessels of the choroid [Amiryan A.G., Brovkina A.F. The nature of the vascularization of mushroom-shaped uveal melanomas // Ophthalmology. - 2005. - Volume 2. - No. 2. - S. 29-32]. If the tumor has a height of more than 5 mm, then the likelihood of this type of blood supply increases significantly. Only transpupillary PDT will not give a full effect. While there is a regression of the apex irradiated transpupillary, the base grows and the tumor returns to its original size ... Thus, only a combination of the two routes of exposure can lead to regression of large tumors.

It is also known that the depth of destruction depends on the length of the laser radiation and the irradiation mode. The longer the laser radiation, the deeper the penetration into the biological object. For comparison: the destruction depth is 3.5 mm — when using radiation with a length of 810 nm in the hyperthermia mode (1 minute of exposure, the spot diameter in the focal plane of 3-5 mm) increases to 10 mm when using radiation with a length of 1060 nm and the regime of photodynamic therapy. Such a significant difference is also explained by fundamental differences in the mechanisms of the biological action of these regimes.

Thus, empirically, the possibilities of destruction of large massifs of the tumor were revealed (height up to 11 mm, base diameter up to 22 mm). They are achieved through the consistent use of several laser radiation sources and access to laser exposure (transpupillary + transscleral), as well as photosensitizers. However, the confined space of the eyeball with its blood-ophthalmic barrier is a serious obstacle to the complete regression of such tumors to a flat chorioretinal scar. Devitalized tumor arrays (conglomerates of non-viable tumor cells with pigmented slag) protrude into the vitreous cavity, are a source of pigment dispersion in the vitreous body with uveogenic potential, and require their radical removal.

Previously, the removal of such tumors was carried out through large incisions in the sclera above the base of the tumor, while the contents of the eye practically poured out, and control over the eye turgor was lost. At the stage of tumor evacuation, the risk of expulsive bleeding from the main vessels of the eye and its choroid, as well as the development of retinal detachment and dislocation of the lens, increased. This significantly reduced the eye's chances of recovery and limited the indications for such organ-preserving treatment methods.

Today, these indications, by contrast, are expanding thanks to vitreoretinal surgery and, in particular, the Accurus 800 CS combined ophthalmic system for vitreoretinal surgery. Vitreoretinal surgery is a unique, slightly traumatic method, when surgical access is performed through dosed mini-incisions in the sclera 23-25G wide in the projection of the flat part of the ciliary body. The advantage of technology is:

- the ability to remove devitalized tumor arrays using vitreotome fragmentation method,

- the ability to control hemostasis using an endocoagulator, which allows you to operate on a "dry field",

- the ability to maintain ablasticity during the operation, which increases the chances of the patient at the vital level,

- the constant control of intraocular pressure during and after surgery, which increases the chances of the eyeball to remain at the organ level,

- the ability to compare the membranes of the eye with the full adaptation of the retina in places of its preservation thanks to endolaser coagulation and silicone or gas tamponade, which allows you to keep the eye at a functional level (residual visual functions).

The objective of the invention is to develop a combined highly effective method for the treatment of intraocular tumors.

Our proposed method consists in the preliminary intravenous administration to patients with intraocular tumors of any photosensitizer and the subsequent conduct of photodynamic therapy at the optimal time, which is determined by the selected photosensitizing agent. In this case, PDT is carried out on a laser with a wavelength at the maximum absorption used by the PS with a total radiation power of 80 to 800 mW / cm ² , carried out first transpupillarly, and then after 3-20 days transsclerally in the same power range using a special the fiber and subsequent endoresection of the non-viable tumor from the side of the vitreous cavity through mini-ports - openings in the sclera in the period from 3 days to 1 month, depending on the time of onset of tumor devitalization.

The minimum dose of photosensitizer administered is determined individually.

The dose of the administered FS, as well as the radiation dose, is determined by the size and degree of pigmentation of the intraocular tumor. The larger the size of the tumor and the greater the pigmentation, the higher the PS and laser power required. A larger tumor array requires the use of large total radiation doses.

At the same time, it was experimentally established that a high single dose exceeding 800 mW / cm ² is associated with an increased risk of cataracts, and at a dose below 80 mW / cm ^{2 the} effects of PDT do not develop [M.V. Budzinskaya “Possibility of using a domestic drug Photosens in fluorescence diagnostics and photodynamic therapy of tumor and pseudotumor eye diseases. ” - Moscow. - 2004. - p. 165. - Thesis for the candidate. honey. sciences].

Irradiation is carried out transpupillary in a standard way [Likhvantseva V.G. Thermotherapy of intraocular tumors. Moscow. - 2009], then after 3-20 days - transsclerally in the same power range after marking the borders of the tumor on the sclera by transillumination, focusing the laser radiation on the pathological focus using a special fiber. In this case, the light guide is positioned at such a distance from the exposure zone that the light beam covers the entire base of the tumor. After tumor devitalization after (3 days - 1 month), simultaneously with total vitrectomy, tumor endoresection is performed, which reduces the risk of systemic metastasis, the risk of relapse and allows you to create conditions for maintaining the remaining uninvolved part of the retina. And consequently, an opportunity is formed to preserve visual functions. Tamponade by substitutes of the vitreous body and laser coagulation of the retina provide a complete adaptation of the membranes of the eye.

Thus, our proposed method of PDT of intraocular tumors allows you to combine PDT "sandwich method" for complete devitalization and avascularization with endovitreal tumor resection.

The advantages of our proposed method is to enhance the therapeutic effect with the expansion of indications for organ-preserving treatment.

The technical result of the invention is a complete radical destruction of the tumor with the expansion of indications for organ-preserving treatment and with the restoration of the functional reserves of the eye.

The technical result is achieved due to the combination of transpupillary and transscleral PDT with tumor endoresection after vitrectomy.

The method is as follows.

A photosensitizer with recommended doses for this pathology is administered intravenously.

PDT is carried out at the time optimal for the accumulation of the taken FS. Use laser radiation with a wavelength at the maximum absorption of the FS.

When FS is accumulated in a tumor, individual planning of the radiation exposure regime is carried out. The radiation power parameters are determined by the tumor array. The larger the thickness of the tumor, the stronger the radiation exposure should be. For tumors with a height of 2 mm, radiation with a power of 80 mW / cm ^{2 is} sufficient. Tumors with a height of 5 mm require large powers, for example, 800 mW / cm ² and are calculated, as shown earlier, individually.

The patient is injected into intubation anesthesia. On the operating table after exposure of the sclera from the conjunctiva at the site of the proposed location of the tumor, transscleral or transpupillary illumination is performed to determine the exact boundaries of the projection of the tumor base on the sclera.

The transscleral effect is carried out according to the marking boundaries using PDT by laser exposure to a laser with a wavelength at the maximum absorption of the FS. Transpupillary PDT exposure is carried out through the pupil. The radiation power varies from 80 mW / cm ² to 800 mW / cm ² for each of the irradiations.

After 3-20 days, depending on the state of the tumor, controlled by various research methods, after the introduction of the photosensitizer, radiation exposure is already carried out transsclerally using a special fiber, forming a light beam with a spot diameter, the dimensions of which capture 1-2 mm of healthy tissues located outside of the marking borders of the projection of the base of the tumor on the sclera.

Then in the hospital after 3-30 days, that is, after tumor devitalization in the conditions of mask or endotracheal anesthesia and local anesthesia with 0.5% alkaine, aseptic treatment of the conjunctival arch with fusidic acid preparations, endovitreal access through mini-ports in the sclera 23-25G wide made in the projection of the flat part of the ciliary body.

Perform total vitrectomy. After that, the devitalized tumor is removed using the vitreotome fragmentation method. After removal of the tumor, complete adaptation of the membranes of the eye with retina fit is achieved using tamponade with vitreous substitutes and laser retinal coagulation. Wounds in the sclera with a width of 23 G are sutured with 8-0 acrylic sutures.

Example 1. Patient C, 65 years old. Diagnosis: choroid melanoma (st.T2N0M0) of the right eye. On the left eye is an initial senile cataract. The initial size of the tumor in height was 6.0 mm, in diameter 17 mm.

The patient was administered Radachlorin at the rate of 0.7 mg / kg of body weight. After 3 hours, transpupillary irradiation of the tumor at a dose of 500 mW / cm ^{2 was} carried out in accordance with the size of the tumor and the nature of pigmentation. 7 days after blanching of the apex of the tumor, the patient was decided to conduct a trans-scleral PDT. Radachlorin was administered at a rate of 0.7 mg / kg body weight. After 3 hours, the patient in the operating room was introduced into intubation anesthesia. On the operating table, after exposure of the sclera from the conjunctiva at the site of the proposed location of the tumor, transscleral illumination was performed to determine the exact boundaries of the projection of the tumor base on the sclera. Marked the boundaries of the projection of the tumor on the sclera. They bred 11 mm from the limb in the sector of 5-7 hours.

Photodynamic therapy was performed transsclerally, with a radiation dose of 500 mW / cm ² . In this case, the light guide was positioned so that the diameter of the light spot in the focal plane of the radiation exposure was 20.0 mm.

After 2 weeks, tumor devitalization took place, which was manifested in the appearance of surface heterogeneity, exudate in the space between the retina and the apex of the tumor and the absence of blood flow (according to ultrasound Doppler ultrasound data) and the visualization of vascular photothrombosis in its stroma. Tumor endoresection was performed through mini-ports in the sclera.

Visual acuity was 0.1 n / corr. Observation for 3 years showed the achievement of stabilization of the process.

Thus, stabilization of the neoplastic process (saving the patient’s life), preservation of the eye as a cosmetic organ (improving the quality of life), and the presence of residual visual functions (functional result) took place.

According to the proposed method, 29 people were treated. All received a positive clinical effect in the form of a flat chorioretinal scar. No complications were noted.

Thus, our proposed combined method of treating intraocular tumors is quite effective, can be used in the practice of ophthalmologists. It can serve as an independent organ-preserving method of treatment, or in combination with other organ-preserving methods.

Claims (1)

A method for organ-preserving treatment of intraocular tumors, including transscleral photodynamic therapy (PDT), characterized in that the transpupillary PDT is preliminarily performed, transscleral PDT is performed 3-20 days after it, and after the tumor is devitalized, total vitrectomy and endoresection of the tumor are performed, the vitreous cavity is replaced vitreous body and carry out laser retinal coagulation.