RU2288740C2 - Organ- retaining method for treating uveal melanoma cases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves administering Wobenzyme combined with brachytherapy with radiomodification and transpupillary thermotherapy or combined with isolated transpupillary thermotherapy. When combined with brachytherapy with radiomodification, Wobenzyme is given 2 days before brachytherapy at a dose of 3 pills 3 times a day with the exception of 8 h before fixation and removal of β-applicator. Next to it, Wobenzyme is given at a dose of 4-6 pills 3 times a day during 3 months. Then, the dose is reduced by 2 pills every month at the fourth, fifth and sixth months. Adjuvant transpupillary thermotherapy is carried out 6 months later after brachytherapy. Wobenzyme is given at a dose of 2-3 pills 3 times a day 2 days before transpupillary thermotherapy. Then, the dose is 4-6 pills 3 times a day during 2 months with following dose reduction by 3 pills every month to prophylactic dose of 1 pill a day. When carrying out isolated transpupillary thermotherapy, Wobenzyme is given in the same mode that it was the case when carrying out adjuvant transpupillary thermotherapy after brachytherapy. To prevent metastasis occurrence, Wobenzyme administration is continued at a dose of 1 pill 7 days every month during the first year and at a dose of 1 pill 3 days every month during the second observation year.

EFFECT: accelerated resorption processes; reduced risk of radiation treatment complications.

Description

The priority in the treatment of the most common malignant intraocular tumor - uveal melanoma - is the isolated or complex application of various methods of influencing the tumor: radiation therapy (brachytherapy, teletherapy with protons, helium ions or gamma rays), surgery (transscleral local resection), laser treatment (photo and laser coagulation, transpupillary thermotherapy, photodynamic therapy), cryotherapy [2, 3, 4]. The use of various methods or their combination allows achieving tumor resorption in 90-93% of patients and reducing the risk of metastasis in the first 5 years to 7-14%, compared with the frequency of metastasis after eye removal - 24-50% [1].

It is well known about the high radioresistance of melanoma tissue to radiation. In addition, due to pathologically altered microcirculation in the tumor, most cells are in a state of chronic hypoxia, as a result of which their sensitivity to the radiation method of exposure is sharply reduced. All this requires exposure to a large total focal dose in a short time. Therefore, this method of radiation exposure is associated with the development of severe complications in a rather high percentage: radiation cataract (66%), proliferative retinopathy (25%), neuropathy (24%), hemophthalmus (23%), secondary neovascular glaucoma (7%); Thus, the effect obtained in organ-preserving treatment is offset by the need for enucleation of the eye.

Among the drugs that improve microcirculation in the tissue, a special place belongs to systemic enzyme therapy drugs that are highly effective and safe, such as wobenzym.

Wobenzym is a mixture of hydrolytic enzymes of plant (papain, bromelain, rutin) and animal origin (trypsin, chymotrypsin, pancreatin, amylase, lipase), which can significantly reduce the infiltration of interstitial space by plasma proteins, increase the elimination of protein detritus and fibrin deposits in the eye. This provides improved microcirculation in the area of damage and a decrease in local edema. Studies conducted in the 60s proved the radioprotective effect of papain by binding of free radical groups [7]. Due to the complex effect on individual components of immunological processes through the effect on cellular and humoral immunity, the ability to break down immune complexes circulating in the blood and fixed on tissues, exert a regulatory effect on complement components and adhesive molecules, as well as a pronounced anti-inflammatory effect and improve blood rheological properties, change general proteolytic activity of blood, enzyme therapy is widely used in the treatment of various diseases, including follows cancer [10].

In the treatment of malignant tumors using the drug of this group, Vobe-Mugos E, the following factors are most significant:

a) suppression of the production of adhesive molecules that contribute to the metastasis of tumor cells and the development of post-radiation complications;

b) increased fibrinolytic activity of blood;

c) an increase in the sensitivity of tumor cells to the effects of radiation therapy and cytostatic drugs [5, 6].

The known scheme for the use of the drug Vobe-Mugos E for malignant tumors [5, 6]: from 6 to 12 tablets per day 30 to 45 minutes before meals, without chewing and drinking plenty of water (200-250 ml). To prevent metastasis, the drug is prescribed 1 tablet per day for 7 days every month for the first year and for 7 days every second month for the second year.

During radiation therapy, the hydrolytic enzymes that are part of the preparations of this group can not only increase the radiosensitivity of the tumor, but also weaken the adverse radiation factors, both in the early and late observation period [9]. Thus, the use of systemic enzyme therapy, namely wobenzyme, in the multicomponent organ-preserving treatment of uveal melanoma is of interest. However, there is currently no data on the technology of use in the treatment of uveal melanoma.

It is known that in order to enhance the effect of brachytherapy, various methods of influencing tumor tissue are used - microwave thermotherapy, laser thermotherapy, laser photocoagulation, systemic administration of cisplatin or iron-59 drugs [2, 4]. But not one of them is aimed at preventing the development of radiation injuries.

The aim of the invention is to increase the effectiveness of multicomponent organ-preserving treatment of uveal melanoma and improve the quality of life of patients by reducing radiation injuries.

This goal is achieved primarily through the use of the scheme and sequence of taking Wobenzym in multicomponent organ-preserving treatment of uveal melanoma, which allows it to be used with a radiomodifying goal, accelerate the processes of resorption of uveal melanoma and reduce the severity of radiation damage to the organ of vision.

This goal is solved due to the fact that with the claimed method for the treatment of uveal melanoma, the drug is prescribed two days before the start of contact transscleral irradiation (brachytherapy), during irradiation 3 tablets 3 times a day 40 minutes before meals, drinking 200-250 ml of water , excluding 8 hours before general anesthesia when fixing and removing the β-applicator, after removing the β-applicator, the dose of the drug is individually selected from 4 to 6 tablets 3 times a day for 3 months (during the formation of early postradiation complications), then the dose lowering m is 2 tablets to 6 months; after transpupillary thermotherapy, both in isolation and in adjuvant treatment after brachytherapy, the drug is prescribed 2-3 tablets 3 times a day for 2 days before transpupillary thermotherapy, then 4 to 6 tablets 3 times a day for 2 months after transpupillary thermotherapy, then the dose is reduced by 3 tablets per month to a prophylactic dose (1 tablet per day); to prevent the development of metastasis after brachytherapy and / or transpupillary thermotherapy, Wobenzym will continue to be taken 1 tablet 7 days a month during the first year, then 1 tablet 3 days a month during the second year of observation.

Studies on patent and scientific and technical sources of information have shown that the proposed method for the treatment of uveal melanoma is not known and does not follow explicitly from the studied level of science and technology, that is, meets the criterion of "novelty." The use of the drug Wobenzym is known in medical practice, however, due to the presence of distinctive actions for their use, sequence of application, we can conclude that the proposed method meets the inventive step.

The proposed method of treatment is as follows.

The patient takes the drug “Wobenzym” 3 tablets 3 times a day 40 minutes before meals, drinking 200-250 ml of water, excluding 8 hours before general anesthesia when fixing and removing the β-applicator, after removing the β-applicator, the dose of the drug is individually selected from 4 to 6 tablets 3 times a day for 3 months, then the dose is reduced by 2 tablets to 6 months. The treatment regimen after transpupillary thermotherapy, both isolated and in adjuvant treatment after brachytherapy, was as follows: the drug is prescribed 2-3 tablets 3 times a day for 2 days before transpupillary thermotherapy, then from 4 to 6 tablets 3 times a day within 2 months after transpupillary thermotherapy, followed by a dose reduction of 3 tablets per month to a prophylactic dose of 1 tablet per day. To prevent the development of metastasis after brachytherapy and / or transpupillary thermotherapy, Wobenzym was continued for 1 tablet for 7 days every month for the first year, then 1 tablet for 3 days every month for the second year of observation.

The method was used in organ-sparing treatment of melanoma of the choroid of the eye itself in 18 patients.

A comprehensive clinical and instrumental examination, which included: visometry, tonometry, perimetry, biomicroscopy, ophthalmoscopy, intravenous fluorescence angiography, ultrasonography with color Doppler mapping, was used to control the effectiveness of the treatment. At the same time, the degree of tumor resorption, change in its size, color, structure, dynamics of blood flow parameters, dynamics of visual functions, course of radiation reactions and the development of complications were evaluated. In addition, a general clinical examination of the patient was performed to detect metastases.

In 18 patients (the study group), multicomponent treatment included: brachytherapy with radio modification with platinum preparations, transpupillary thermotherapy and wobenzym.

In 22 patients (control group), brachytherapy with radiomodification by platinum preparations and subsequent transpupillary thermotherapy was performed without the use of Wobenzym. In both groups, patients were comparable in stages of the process.

In the study group, after 6 months, complete resorption of the tumor with the formation of an atrophic scar was observed in 4 patients (22%), partial resorption (decrease in tumor elevation more than 50% of the initial) in 11 patients (61%), stabilization of the process (reduction in tumor size less 50% of the initial size, stabilization or increase in its size by no more than 25%) - in 3 patients (17%). After 12 months, complete resorption of the tumor was observed in 15 patients (83%), partial resorption (decrease in tumor elevation by more than 50%) in 3 patients (17%). The residual tumor in 3 patients, constituting up to 15-20% of the initial one, was subjected to laser treatment - transpupillary thermotherapy. In the outcome, after 3-6 months, a complete tumor regression was observed in all patients.

In the control group, after 6 months, complete resorption of the tumor with the formation of an atrophic scar was observed in 4 patients (18%), partial resorption in 12 patients (55%), stabilization of the process in 6 patients (27%). After 12 months, complete resorption of the tumor with the formation of an atrophic scar was observed in 14 patients (64%), partial resorption in 6 patients (27%), stabilization of the process in 2 patients (9%), progression was not observed. The residual tumor in 6 patients, constituting up to 15-35% of the initial, and in 2 patients, constituting 50-70% of the initial, was subjected to laser treatment - transpupillary thermotherapy. In the outcome, after 5-10 months, complete regression of the tumor was observed in 5 patients, partial regression in 3 patients, the progression of the process was not observed.

The clinical result obtained is confirmed by ultrasonographic studies, indicating a decrease in the acoustic density of the tumor and a decrease in blood flow before it is absent in the study group at an earlier date (up to 6 months) than in the control group. Local and systemic metastasis with periods of observation up to 3 years in both groups was not observed.

A study of postradiation complications in both groups showed that in the study group they were observed in 4 patients (18%): retinovasculitis -2 (11%), neuroretinopathy - 1 (5.5%), neovascular glaucoma - 1 (5.5%) . In the control group, postradiation complications were observed in 9 (41%) patients: conjunctival necrosis - 1 (4.5%), conjunctiva necrosis followed by scleral necrosis - 1 patient (4.5%), rectal paresis - 2 (9%) neuroretinopathy - 2 (9%), cataract - 3 (14%).

After transpupillary thermotherapy, no complications were observed in the study group. In the control group, complications were noted in 5 patients (62.5%): large vessel occlusion of the mixed type in 4 patients (40%), partial hemophthalmus in 1 patient (12.5%).

In clinical studies of the effect of wobenzym on the body during multicomponent organ-preserving treatment of melanoma of the choroid itself, the following were established: strengthening and accelerating the process of tumor destruction, faster rates of regression of formation, reducing complications, improving the vital prognosis and quality of life of patients.

All patients noted the good tolerance of the drug Wobenzym, the absence of allergic reactions, and an improvement in well-being.

We present clinical examples of the use of the prototype (example 1) and the proposed method (examples 2, 3).

Example 1. Patient Yu, 74 years old. Diagnosis: Melanoma of the choroid of the left eye T3N0M0. Ophthalmoscopically in the central parts of the fundus of the optic nerve head - a yellowing-grayish proging focus from 12 to 3 hours, with a tuberous surface, single hemorrhages, perifocal retinal detachment. According to ultrasound data with color Doppler mapping, the formation of an inhomogeneous structure, with a base width of 11.1 mm, a prominence of 7.0 mm, is determined by juxtapapillary blood flow with color Doppler mapping from low to high speed, medium and high resistance. Brachytherapy was performed; the total focal dose was 132 Gy. 3 months after the treatment, a slightly positive dynamics was observed, which was clinically determined in the form of a decrease in the size of the tumor, which was confirmed by ultrasound data with color Doppler mapping (formation with a base width of 9.5 mm, a 5.1 mm prominence, own blood flow - low-speed, highly resistant ) 5 months after treatment, the patient developed post-radiation cataract, which led to a sharp decrease in vision to the correct light projection and the impossibility of ophthalmoscopic control of uveal melanoma. After 6 months after treatment, according to the ultrasound examination, the formation of the previous sizes. For organ-preserving purposes, repeated transscleral irradiation of uveal melanoma was performed.

Example 2. Patient D., 59 years old. Diagnosis: Melanoma of the choroid of the left eye T3N0M0. Ophthalmoscopically in the lower external segment of the fundus is an exophytic glassy-mediated formation of a dark gray color from 3 to 6 hours, with a tuberous surface, above it a flat retinal detachment. According to the data of ultrasound with color Doppler mapping in the lower-outer segment, the formation of a moderately heterogeneous echostructure is determined, the width of the base is not less than 11 mm, the prominence is 8.6 mm, with color Doppler mapping the blood flow is medium-speed, medium-resistant. An episcleral fixation of an ophthalmic applicator was carried out with the preliminary administration of cisplatin 100 mg with a radio-modifying target, the total focal dose - 128 Gy. I took Wobenzym according to the scheme: 2 days before fixing the β-applicator 3 tablets 3 times a day 40 minutes before meals, over the next 3 months 5 tablets 3 times a day and a gradual dose reduction to 9 tablets per day the beginning of 7 months. 6 months after the treatment, pronounced positive dynamics was observed in the form of a decrease in tumor tissue in area and height, the formation of atrophy of the choroid around a residual tumor, and a decrease in retinal detachment. According to the data of an ultrasound study with color Doppler mapping, the formation was determined with a base width of up to 7.8 mm, a 2.7 mm prominence, and blood flow in the projection of the focus on the verge of artifacts. 6 months after brachytherapy, transpupillary thermotherapy for a residual tumor was carried out and the term of taking Wobenzym was extended by 3 tablets 3 times a day for 2 months after transpupillary thermotherapy with a subsequent dose reduction of 3 tablets monthly to a prophylactic dose of 1 tablet per day. To prevent the development of metastasis, Wobenzym was continued for 1 tablet for 7 days every month for the first year. 3 months after transpupillary thermotherapy, a dark-gray color of a small prominence lesion with areas of fibroplasia on its surface is clinically determined against the background of an atrophic scar, there is no retinal detachment. According to a comprehensive ultrasound examination, the width of the base is up to 6 mm, with a prominence of 1 mm, blood flow in the projection of the focus is not determined. In the follow-up period up to 12 months, a complete regression of the tumor was obtained, signs of early and late complications were not noted. Visual acuity before and after treatment was 0.8.

Example 3. Patient 3., 50 years. Diagnosis: Melanoma of the choroid of the right eye T2N0M0. Clinically, juxtapapillary, at the upper border of the optic nerve disk, a gray tuberous formation with single point hemorrhages on the surface is ophthalmoscopically gray, a flat retinal detachment above it. According to the data of an ultrasound study with color Doppler mapping upward from the visual disc, a formation with a base width of 8–9 mm, a measure of 4 mm is determined, the height of the retinal detachment is up to 1 mm; own vessels in the tumor are recorded, the blood flow is medium speed, medium resistant. An isolated transpupillary thermotherapy was carried out with a preliminary intake of Wobenzym for 2 days, 3 tablets 3 times a day, then 6 tablets 3 times a day for 2 months after transpupillary thermotherapy, followed by a dose reduction of 3 tablets monthly to a preventive dose of 1 tablet per day. To prevent the development of metastasis, Wobenzym was continued for 1 tablet for 7 days every month for the first year. At the follow-up examination after 3 months, positive dynamics were noted: ophthalmoscopic reduction in the size of the tumor in area and height, the appearance of brick-colored patches, and retinal detachment. The clinical picture is confirmed by ultrasound data - upward from the optic nerve disk formation with a base width of 6 mm, a prominence of 3.2 mm, blood flow on the verge of artifacts. 6 months after transpupillary thermotherapy, a focal area with clear boundaries is clinically observed in light gray with a small prominence, according to complex ultrasound, the prominence is 1.8 mm, blood flow is not determined. After 10 months, a complete tumor regression was obtained. No complications were noted. Visual acuity before treatment was 0.4, after treatment 0.3.

Thus, the claimed invention is aimed at improving the effectiveness of multicomponent organ-preserving treatment of uveal melanoma and improving the quality of life of patients by reducing radiation injuries.

Literature:

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Claims (1)

A method of organ-preserving treatment of uveal melanoma by multicomponent exposure, characterized in that wobenzym is administered in combination with brachytherapy with radiomodification and transpupillary thermotherapy or in combination with isolated transpupillary thermotherapy, while in case of brachytherapy with radiomodification, 3 times a day, 3 tablets are administered with 2 wobenzyra once a day, excluding 8 hours before fixing and removing the β-applicator, after which 4 to 6 tablets are administered wobenzym 3 times a day for 3 months, then a dose of sn they are pressed for 2 tablets monthly on the 4th, 5th and 6th months, then 6 months after brachytherapy adjuvant transupillary thermotherapy is carried out, and two days before transupillary thermotherapy, wobenzym is administered 2-3 tablets 3 times a day, and after it for 2 months, 4-6 tablets 3 times a day, followed by a dose reduction of 3 tablets per month to a prophylactic dose of 1 tablet per day; in the case of an isolated transpupillary thermotherapy, wobenzym is administered according to the same scheme as with adjuvant transpupillary thermotherapy after brachytherapy; to prevent the development of metastasis, as in the case after brachytherapy and transpupillary thermotherapy, as well as in the case of isolated transpupillary thermotherapy, the introduction of Wobenzym continues 1 tablet 7 days a month for the first year, and 1 tablet 3 days a month for the second year of observation.