RU2448745C2 - Method of treating superficial urinary bladder cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, oncologic urology and can be used for treatment of superficial urinary bladder cancer. For this purpose in one session procedures of carrying out fluorescent diagnostics and photodynamic therapy are combined. For this purpose 1-1.5 hours before operation through urethral catheter into urinary bladder cavity photoditazine in dose 5 mg per 20 ml of physiological solution is introduced. After that, fluorescent cytoscopy and transurethral resection of detected lesions and photodynamic therapy of fluorescent parts of mucous membrane are performed. Tumour is aimingly irradiated with application of irradiator with output power of optic element 100 mW by light energy 60-80 J/ cm² and wavelength 402 nm. While carrying out fluorescent cytoscopy fluorescent lesions of urinary bladder mucosa are identified and resection of mucosa sections with distinct contours of fluorescence is performed. Fluorescence control is performed until there is clear reduction of fluorescence intensity.

EFFECT: method makes it possible to increase treatment efficiency due to combination in one procedure carrying out FD and PDT with application of one photosensitiser and increase of sections of radical resection of mucosa with distinct fluorescence contours with simultaneous visual control, as well as makes it possible to reduce luminous flux output.

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Description

The invention relates to medicine, more specifically to oncourology, and can be used in the examination and simultaneous treatment of patients suffering from superficial bladder cancer.

Bladder cancer is one of the most common oncourological diseases. More than 150 thousand new cases of the disease are registered annually in the world. In Europe, a tumor of this localization takes 5th place in men and 11th in women in frequency among all malignant neoplasms. In Russia, the number of patients with bladder cancer increases annually and over the past 10 years, the incidence rate per 100 thousand people in Russia has increased 1.5 times (Apolikhin O.I., Sivkov A.V. et al. - 2008, Incidence of the Russian population in 2006 : Statistical materials: in the second hour - M .; 2007, Axel E.M. - 2005, Laurent O.B. - 2007). At the same time, people whose body is exposed to aromatic amines, as well as people suffering from chronic cystitis, are at risk.

According to the clinical classification of bladder cancer, superficial (T1-2) include tumors that do not extend beyond the mucous layer (TNM classification of malignant tumors. / Ed. By Sobin, Wittekind. Fifth edition. - New-York: Wiley-Liss , 1997).

Despite the achievements of modern oncology, the problem of treating malignant neoplasms, in particular superficial bladder cancer, cannot be considered resolved. Treatment is successful for most patients only in the initial stages of cancer. However, at the time of diagnosis, 2/3 of the patients have a far-reaching process, and only half of them undergo special treatment (Oncological care for the population of Russia in 2008 / Edited by V.I. Chissov, V.V. Starinsky, G. .V. Petrova. M., Federal Research Institution named after P. Herzen of the Russian Medical Technologies. 2009. 192 p. Schenkman E., Lamm DL Superficial bladder cancer therapy. Sci World J 2004; 4 (Suppll): 387-99 ) But the possibilities of surgical, radiation, combined and even complex treatment in such a situation are limited. The cure rate and five-year survival rate is not more than 10% (Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 2007; 18: 581-92 .; Silverman DT, Devesa SS, Moore LE, Rothman N. Bladder cancer. In: Schottenfeld D, Fraumeni JrJF, editors. Cancer epidemiology and prevention. New York: Oxford University Press; 2006. p.1101-27; Kiemeney LA Familial bladder cancer. In: Lemer SP, Schoenberg M, Sternberg C, editors. Textbook of bladder cancer. London: Taylor & Francis - Informa; 2005. p.19-26 .;) In the vast majority of them, even after intensive treatment in the next 1-2 years, relapses occur in the area of operation or distant metastases, from which the patients die (Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology 2005; 66: 4-34.). For these patients, until the last decade, an adequate method of treatment did not exist.

It is known that the possibilities of modern oncology have expanded significantly with the advent of photodynamic therapy (hereinafter - PDT), which is a fundamentally new method of treating malignant neoplasms, based on the use of photodynamic damage to tumor cells during the photochemical reaction. PDT is a two-component treatment method, one of the components of which is light exposure, the other component is a photosensitizer - a substance that selectively accumulates in a cancerous tumor and stays in it longer than in normal or healthy tissues, and almost does not stay in the surrounding healthy tissues (Allison B.A., Pritchard PH., Levy JG Evidence for low-density lipoprotein receptor-mediated uptake of benzoporphyrin derivative // Br. J. Cancer. - 1994. - V.69. - P.833-839 .; Allison BA, Piitchard PH, Richter AM, Levy JG The plasma distribution of benzoporphyrin derivative and the effects of plasma lipoproteins on its biodistribution // Photochem. Photobiol. - 1990. - V.52. - P.501-507 .; Chen Q., Huang Z., Chen H., Shapiro H., Beckers J., Hetzel FW Improvement of Tumor Response by Manipulation of Tumor Oxygen- ation During Photodynamic Therapy // Photochem Photobiol. - 2002. - Vol. 76. - P.197-203).

In recent years, PDT using various photosensitizers has been successfully used for malignant neoplasms in urology, in particular for the treatment of superficial bladder cancer. (Sorokaty A.E., Yagudaev D.M., Markova M.V. Photodynamic therapy in urology // Laser medicine. - 2006. - V. 10. - Issue 3. P.58-61 .; Geynits A. V., Sorokaty AE, Yagudaev DM, Trukhmanov RS Photodynamic therapy. History of the method and its mechanisms // Laser Medicine. - 2007, V.11. Issue 3 p. 42; Yagudaev D. M., Bulgakova N.N., Sorokaty A.E., Geynits A.V. Fluorescence diagnosis of bladder cancer // Laser Medicine. - 2007, V.11, issue 2, p. 39).

It should be noted that the peculiarity of PDT is the need to limit the light regime for a rather long time from the moment of administration of photosensitizers, which is associated with photosensitivity of the skin and the development of possible complications in this regard.

The PDT method of superficial bladder cancer compares favorably with traditional methods for treating malignant tumors (surgery, radiation and chemotherapy) with high selectivity, no risk of surgery, severe local and systemic complications of treatment, the possibility, if necessary, of repeated treatment sessions and, especially importantly, a combination of fluorescence diagnostics and therapeutic effects in one procedure. In addition, in most patients, one course of PDT is sufficient to eradicate the tumor, which can also be done on an outpatient basis (Moan J., Peng Q., Iani V. Et al. Biodistribution, pharmacokinetic and in vivo fluorescence spectroscopic studies of photo sensitizers // SPIE. - 1995. - Vol.2625 - P.234-248).

A known method of photodynamic therapy of superficial bladder cancer (RF patent No. 2290230, 2006), in accordance with which the tumor is locally irradiated with a laser with an output power of 0.5-2 W, a wavelength of 662 nm and a light energy of 300-600 J / cm ² in during 10-30 min in the presence of a photosensitizer of photoditazine, administered intravenously at a rate of 0.8-1 mg / kg Then, a silicone balloon with a fiber optic fiber with a cylindrical diffuser is inserted into the bladder. The balloon is filled with distilled water and laser irradiation of the entire bladder mucosa is continued with a light energy of 30-40 J / cm ² for 40-60 minutes.

It must be emphasized that according to the invention described in RF patent No. 2290230, PDT of bladder cancer is performed using a laser light source with a wavelength of 662 nm (red spectrum), which completely excludes the diagnosis.

In addition, the disadvantages of the method described in the patent of the Russian Federation No. 2290230 include the fact that local exposure to bladder tumors is carried out “blindly”, that is, irradiation of the tumor is carried out without visual inspection, and the foci are preliminarily determined clinically by conventional cystoscopy. Due to the fact that in the known method, the photosensitizer Photoditazine is administered intravenously, its accumulation in the tumor tissue leaves much to be desired, while the likelihood of complications (photosensitivity, allergic reactions, etc.) increases.

It is known that tumors of this localization are characterized by a multiplicity of lesions, some of which may not be detected during standard cystoscopy without using PDT. In this regard, local exposure to the mucous membrane of the bladder without targeted irradiation of the affected area leads to a high incidence of relapse, due to the fact that hidden foci of cancer were not detected during standard cystoscopy and, accordingly, were not removed, and when irradiated into this zone The mucous membrane was not supplied with sufficient light energy.

A known method of treating superficial bladder cancer, selected as the closest of the analogues (RF patent No. 2346657), by conducting PDT using fluorescence diagnostics (hereinafter - PD) in accordance with which to conduct PD and PDT administered intravenously 48 hours before surgery photosensitizer photogam. Alasens photosensitizer is then administered 2 hours before surgery into the bladder. During the operation, PD is performed with alasens, and the boundaries of the fluorescence of tumors visible during cystoscopy and the foci of fluorescence of latent cancer are determined. The revealed fluorescence boundaries of all tumors are marked by coagulation of these boundaries along the perimeter of the fluorescence foci. Then carry out PDT. Moreover, the entire bladder is irradiated. After this, transurethral resection of tumors (hereinafter - TUR) is performed with the removal of all foci according to the marking.

In the known method, PD and PDT are combined in one procedure, for which a photosensitizer photogam is administered intravenously for 48 hours, and then 2 hours before surgery, an alasens photosensitizer is introduced into the bladder, followed by TUR of the tumors.

The disadvantages of the method described in the patent of the Russian Federation No. 2346657 include the complexity of the technique, combining the introduction of two photosensitizers (photogem and alasens), which increases the likelihood of negative effects on the body (photosensitivity, allergic reactions, etc.) and significantly complicates the procedure itself , and also, in addition, increases the cost of treatment.

In addition, it should be especially noted as a disadvantage that according to the method described in the patent of the Russian Federation No. 2346657, FTD is carried out without simultaneous visual inspection.

Given the known requirements for PDT of bladder cancer, such as: the selectivity of the photosensitizer to a tumor of the bladder; the need for light exposure on the entire surface of the bladder mucosa; dosimetry parameters confirmed by studies and depending on the burnout time of the photosensitizer (photobleaching or photobleaching). And also given the fact that for PD, a wavelength of 400 to 430 nm is used. In this case, fluorescence is determined in a spectrum of about 730 nm, visible as a red glow, the authors had to find a sufficiently powerful source of monochrome light in the maximum absorption spectrum and an output power in the irradiation zone of at least 50 mW.

In this regard, the problem to be solved by the present invention is directed, is to develop a method for the treatment of superficial bladder cancer, which improves treatment efficiency by increasing the foci of radical removal of superficial bladder cancer, reducing the frequency of relapses and adverse reactions.

The technical result achieved by using the proposed method for the treatment of superficial bladder cancer is to increase the effectiveness of treatment by combining in one procedure PD, PDT using one photosensitizer and increasing the sites of radical resection of the mucous membrane with clear fluorescence contours with visual inspection due to the following :

- local or targeted irradiation of the tumor with light of a certain wavelength corresponding to the absorption peak of the photosensitizer, as a result of which a photochemical reaction begins in the tumor with the formation of singlet oxygen and oxygen free radicals that have a toxic effect on the tumor cells;

- exposure to the photosensitizer molecule with light with a certain wavelength, which leads to the formation of free radicals or atomic oxygen, which irreversibly damage the membranes, DNA and other cellular structures of the tumor;

- intravesical administration of the photosensitizer in the form of a neutral solution, which avoids systemic complications and creates the prerequisites for the effective penetration of the photosensitizer into the tumor by diffusion;

- selective accumulation of the photosensitizer in the tumor tissue and directed, local, clearly limited monochrome irradiation, which ensures the locality of the photodynamic damage to the tumor; while the tumor is resorbed and gradually replaced by connective tissue;

- the implementation of visual control over the procedure, which eliminates the change of endoscopic equipment and illuminator;

- conducting fluorescence cystoscopy to monitor the effectiveness of diagnosis and resection.

The problem is solved, and the technical result is achieved by the fact that the proposed method for the treatment of superficial urinary cancer involves combining in one session the procedure for conducting fluorescence diagnostics and photodynamic therapy using intravesical photosensitizer and subsequent fluorescence cystoscopy and transurethral resection of the identified lesions and photodynamic therapy of mucosal fluorescence shells, moreover, as a photosensitizer use photoditazine, which is injected into the bladder cavity 1-1.5 hours before surgery through a urethral catheter at a dose of 5 mg per 20 ml of physiological saline, the tumor is targeted by irradiation using an emitter with an output power of an optical element of 100 mW, light energy of 60-80 J / cm ² and wavelength of 402 nm, which corresponds to the maximum absorption peak Photoditazin administered intravesically and the formation of free radicals or atomic oxygen, which irreversibly damage the tumor cell structure, wherein during the luorestsentnoy cystoscopy determined fluorescing lesions bladder mucosa and carried portions mucosal resection with precise contours of fluorescence and fluorescent monitoring is performed as long as the mark is not visually distinct decrease in fluorescence intensity.

According to the invention, a mercury illuminator equipped with light filters for a wavelength of 402 nm is used.

According to the invention, objective monitoring of the effectiveness of therapy is carried out using morphological studies of resected tissues at the beginning of the irradiation session and after its completion.

According to the invention, in the postoperative period after 6-8 weeks, control studies are carried out by conducting fluorescence cystoscopy.

The proposed method for the treatment of superficial bladder cancer differs from the known ones in that:

- the photosensitizer photoditazine is administered intravesically, which reduces the likelihood of complications (photosensitivity, etc.), and for the first time it is proposed to use a solution of photoditazine for intravesical administration in order to conduct PD and PDT;

- to excite the photosensitizer of photoditazine, monochrome light of a high-power mercury illuminator is used, and not a laser light source, so there is no need to use different light sources during the procedure;

- it is proposed to use the same wavelength (402 nm) for both PD and PDT, while there is no need to divide the time by diagnostics, and then “blindly” conduct phototherapy;

- PDT is carried out simultaneously with the beginning of PD and continues at the stage of resection of the fluorescent lesions, while the exposure time is limited only by the rate of fading of fluorescence (photo-bleaching), because exposure to light with a specific wavelength on the photosensitizer molecule of photoditazine leads to the formation of free radicals or atomic oxygen, which irreversibly damage membranes, DNA and other cellular structures;

- the spectrum of the light source used corresponds to the maximum “peak” of absorption of the photosensitizer of photoditazine, which allows simultaneous diagnostics to conduct photodynamic therapy, which in turn allows for a lower light flux to achieve the same high degree of excitation of the photosensitizer molecule as with more powerful laser radiation, but at the next peak of absorption.

The invention is illustrated by figures.

Figure 1 shows the electronic absorption spectrum of the photosensitizer photoditazine, where λ is the wavelength, nm, and D is the absorption intensity.

Figure 2 presents a photograph showing an objective control of the effectiveness of diagnosis and resection.

Figure 3 presents a photograph showing an objective control of the effectiveness of therapy after the procedure.

In the electronic absorption spectrum of photoditazine (see Figure 1), five characteristic absorption bands are observed with maximums at wavelengths of 400 ± 2 nm, 504 ± 2 nm, 534 ± 2 nm, 608 ± 2 nm, 662 ± 2 nm. The maximum "peak" absorption occurs at a wavelength of 402 nm, while the energy cost of excitation can be 3 times less than in the spectrum of 660 nm.

To illustrate the invention, the following is a clinical example (extract from the medical history), confirming the clinical effect achieved by the treatment of the proposed method.

Example

Patient N., 67 years old, case history No. C-36, was admitted to the Department of Urology of OrKley Hospital on 11.01.2010, again, with a diagnosis of Bladder cancer (pTin situN0M0). The patient complained of discomfort and pain during urination, an occasional admixture of blood in the urine. Considers himself ill for more than 3 years. Repeatedly underwent courses of treatment for chronic cystitis, which brought temporary relief. In December 2009, he was hospitalized in the OrKli hospital, where the diagnosis was made on the basis of the examination: ultrasound and fluorescence cystoscopy and biopsy of the bladder wall with fluorescence control from 12/15/2009 (histological analysis No. C-21vg from 12/18/2009 - cancer foci in situ on the background of granular cystitis). A standard examination, including a fluorogram of the chest organs, ultrasound of the liver and kidneys, skeleton osteoscintigraphy, pathology and signs of distant metastasis were not detected. General blood test from 02/11/10, HB 131 g / l. Er. - 4.0 × 10 ¹² / l, CPU. 0.9; Lake - 6.4 × 10 ⁹ / l, eos. - 2%, fell. - 1%, seg. - 58%, lymph. - 31%, mon. - 8%, ESR - 30 mm / h; urinalysis: color - straw yellow, density - 1021, pH 7.5, protein - 0.33 g / l, glucose - no, white blood cells - 3.0 × 10 ⁹ / l, red blood cells - 4.0 × 10 ⁹ / l

Given the clinical course of the disease, objective examination data and a medical history, the patient was treated with bladder cancer. For this, the following tools and materials were used: endovideo surgical stand for Karl Storz; endoscopic mercury illuminator (equipped with special filters for a wavelength of 402 nm); Resectoscope with an optical element from Karl Storz; photosensitizer for topical use photoditazine (manufactured by VETA-GRAND Russia LLC).

On the day of admission, after a preliminary examination, the patient underwent the following procedures: 5 mg photoditazine solution per 20 ml of physiological saline was injected intraperitoneally through the urethral catheter 1.5 hours before the planned procedure, including irradiation with simultaneous PD and PDT and resection. In the operating room, under intravenous anesthesia, a fluorescence cystoscopy was performed, in which fluorescent lesions of the mucous membrane of the bladder were determined, occupying about 40% of the entire surface of the mucous membrane. Then, under fluorescence control, a resection of the affected areas of the mucous membrane revealed during diagnosis was performed with clear contours of fluorescence.

In this case, fluorescence control was visually carried out in the 402 nm spectrum with a radiation power at the output of the optical element of 100 mW and a light energy of 60-80 J / cm ² , which corresponds to the absorption peak of the introduced intravesical photosensitizer of photoditazine and the formation of free radicals or atomic oxygen, which irreversibly damage cellular tumor structure.

Fluorescence control was carried out visually until there was a distinct decrease in fluorescence intensity, indicating a complete "burnout" of singlet oxygen (see Figure 2).

Objective monitoring of the effectiveness of therapy is carried out using morphological studies of resected tissues at the beginning of the irradiation session and after its completion.

In morphological material, an increase in the degree of damage to cell structures after irradiation was noted.

At the end of the procedure, a Foley catheter was inserted into the urethra to control hemostasis in the bladder cavity. The next day, the catheter was removed and the patient was discharged for outpatient treatment. According to the results of a histological examination (Gitology No. C-092 dated 01/14/10), two preparations were diagnosed with carcinoma in situ against the background of granular cystitis.

In the postoperative period, complications and negative manifestations were not noted. Specific therapy was not performed. The patient was given only symptomatic therapy (non-steroidal anti-inflammatory drugs for painful urination).

The patient after treatment by the proposed method re-entered the department after 6 weeks for follow-up examination. A control fluorescence cystoscopy with a biopsy of the bladder wall was performed. When fluorescence cystoscopy, specific fluorescence was not observed, according to the histological conclusion (Histology No. C-1276 from 02.24.10), tumor tissue was not found in the presented preparation, as illustrated in Fig. 3.

The patient undergoes clinical observation. During the control cystoscopy 3 months after the operation, no tumor recurrence was detected.

During the observation of negative manifestations were noted.

Thus, an example illustrating the invention clearly demonstrates the achievement of a technical result consisting in increasing the effectiveness of treatment by combining in one procedure PD, PDT using one photosensitizer and increasing sections of the mucosal resection with clear contours of fluorescence, while conducting visual inspection in visible spectrum with a wavelength of 402 nm, a radiation power at the output of the optical element of 100 mW and a light energy of 60-80 J / cm ² .

Claims (4)

1. A method of treating superficial bladder cancer, comprising combining in one session the procedure for conducting fluorescence diagnostics and photodynamic therapy using an intravesical photosensitizer and subsequent fluorescence cystoscopy and transurethral resection of the revealed lesions and photodynamic therapy of fluorescent mucous membranes, which differs in photosensitizers use photoditazine, which is injected into the bladder cavity in 1-1.5 hours through the operation of the urethral catheter at a dose of 5 mg per 20 ml of physiological saline, and the tumor is irradiated with sighting radiator with an output of 100 mW optical element, the light energy of 60-80 J / cm ² and wavelength of 402 nm, which corresponds to the maximum absorption peak photoditazine introduced intravesically and the formation of free radicals or atomic oxygen, which irreversibly damage the tumor cell structures, while fluorescence foci are determined by fluorescence cystoscopy by CONTROL bladder mucosa and carried portions mucosal resection with precise contours of fluorescence, and fluorescence monitoring is carried out as long as the mark is not visually distinct decrease in fluorescence intensity. 2. The method according to claim 1, characterized in that they use a mercury illuminator equipped with light filters for a wavelength of 402 nm. 3. The method according to claim 1, characterized in that the objective control of the effectiveness of therapy is carried out using morphological studies of resected tissues at the beginning of the irradiation session and after its completion. 4. The method according to claim 1, characterized in that in the postoperative period after 6-8 weeks, control studies are carried out by conducting fluorescence cystoscopy.

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