RU2682293C2 - Method for treating lung cancer - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to medicine, namely to oncology, and can be used to treat lung cancer. For this purpose, endoscopic photodynamic therapy (PDT) is performed. First, the Fotolon photosensitizer is administered in a dose of 1.1 to 1.4 mg/kg of the patient's body weight intravenously over a period of 30 to 40 minutes. 3 hours after the photosensitizer is injected, a laser irradiation of the intrabronchial/intratracheal tumor component is performed. After PDT, cytostatic chemotherapy is administered according to the following scheme: Cisplatin 120 mg on the first day and Etoposide 200 mg on 1, 2, 3 day or Carboplatin 600 mg on the first day and etoposide 200 mg on 1, 2, 3 days. Treatment cycle is repeated 2-3 times with an interval of 21 to 28 days. Then remote radiation therapy in a single focal dose of 2 Gy or 2.4 Gy to a total focal dose of up to 60 or 70 Gy is performed.EFFECT: method provides improved immediate and long-term results of treatment and local control of inoperable non-small cell lung cancer with obstructive ventilation disorders by reducing the tumor mass, restoring airway patency, reducing the symptomatic manifestations of the disease.1 cl, 4 dwg, 2 ex

Description

The present invention relates to medicine, is intended for the treatment of cancer. It mainly relates to the treatment of locally advanced malignant tumors of the bronchi.

From the literature it is known that lung cancer is one of the most common forms of malignant tumors and a leading cause of cancer mortality in men. An insignificant difference in the number of sick and dead characterizes an unfavorable prognosis of the disease and makes lung cancer one of the most important medical and socio-economic problems. The most effective treatment for non-small cell lung cancer is considered to be radical surgery, but only 15-25% of patients are operable at the time of diagnosis. Most of the patients with lung cancer at the time of diagnosis are recognized inoperable due to the significant prevalence of the process, its complicated course or severe concomitant diseases. Traditional conservative methods of treatment do not allow satisfactory results. In addition, in a significant proportion of patients they are not possible due to existing or potential complications and poor somatic status of patients. This contingent of patients necessitates a wider use of alternative methods of treatment.

The known method of "Photodynamic therapy (FTD) in the combined treatment of lung cancer stage III" [Akopov A.L., Rusanov A.A., Molodtsova V.P., Chistyakov I.V., Kazakov N.V., Urtenova M. A., Ryde M, Papayan G.V. Photodynamic therapy in the combined treatment of stage III lung cancer // Surgery. Magazine them. N.I. Pirogov. 2013. No3. S. 17-20]. In this method, at the stage of polychemotherapy, in addition to the introduction of cytotoxic chemotherapy drugs, patients underwent PDT with chlorine photosensitizers. According to the authors, this method is safe and effective, it allows to increase the number of patients who can undergo surgical treatment with a reduction in resection.

The disadvantages of the method are that this type of treatment was used in potentially operable patients and cannot be used in inoperable patients.

The known method “Combinations of PDT and LT in the treatment of lung cancer” [Ragulin Yu.A., Kaplan MA, Medvedev V.N., Afanasova N.V., Kapinus V.N. Combined PDT and LT in the treatment of lung cancer // Russian Biotherapeutic Journal. 2011. V. 10. No. 2. S. 33-36]. The method combines photodynamic and radiation therapy for inoperable lung cancer. The peculiarity of the method lies in the fact that radiation therapy was carried out by crushing the daily dose of 2.5 Gy into two fractions of 1 Gy and 1.5 Gy with an interval of 4-5 hours, and PDT was performed with chlorine-type photosensitizers (Photolon, Photoditazine) for 10- 14 days before the start of radiation therapy.

The disadvantages of the method are the lack of multi-course induction treatment with the inclusion of cytostatic chemotherapy, which led to a limitation of the therapeutic effect.

The prototype of the proposed technical solution is the "Method of complex treatment of locally advanced malignant tumors of the bronchi and / or trachea" according to patent RU 2372119 (05.15.2008). The method includes conducting argon plasma recanalization of the lumen of the bronchi and / or trachea, at a power of 60-90 W, followed by photodynamic therapy with a photoditazine preparation of 1.5 mg / kg, radiation from a semiconductor laser with a wavelength of 662 nm with a power density of 300 mW / cm2 and the total dose of energy 400 J / cm2, combined radiation therapy, including brachytherapy with a length of the source path of 5-20 cm, a step of 5 mm and a reference isodose depth of 10 mm from the source; with the provision of the applicator movement above and below the tumor from 1 to 3 cm and dose adjustment from 14 to 28 Gy in the regimen of 1 time per week for 7 Gy and remote radiation therapy in the regime of 5 times a week for 1-2 Gy to SOD 45-55 Gr on the background of irradiation with intravenous infusions, 4 courses of chemotherapy are carried out: cisplatin at a dose of 100 mg / m2 for 1 day with gemcitabine at a dose of 1000 mg / m2 for 1, 8, 15 days with an interval of 4 weeks, or cisplatin at a dose of 80 mg / m2 on day 1 with etoposide at a dose of 120 mg / m2 on days 1, 3, 5 with an interval of 3 weeks.

The disadvantages of the method is the lack of application of induction multi-course treatment, and they try to obtain the radical effect of radiation exposure by combining brachytherapy of 14-28 Gy and remote radiation therapy of 45-55 Gy.

The technical result of the invention consists in expanding the possibility of treating a contingent of patients with inoperable non-small cell lung cancer, including those in an initially unsatisfactory condition.

Currently, various methods of conservative treatment of inoperable non-small cell lung cancer are used, which may include various combinations of radiation and drug antitumor effects.

Moreover, it should be taken into account that the mutually conditioned use of various influences leads to the elimination of the tumor. In this case, it is necessary to potentiate the advantages of the methods used and minimize their disadvantages. So PDT has a highly effective local effect, but does not directly affect micrometastases in adjacent tissue and regional collectors. At the same time, radiation therapy quite productively affects locoregional micrometastases, but, in some cases, does not reach its full effect when exposed to the tumor itself. Cytostatic chemotherapy implements both a direct antitumor effect and has a pronounced radiosensitizing effect. Given these circumstances, it seems possible and very promising combination of radiation therapy, chemotherapy and PDT.

Moreover, the induction of PDT and chemotherapy for patients with endobronchial tumor obstruction can improve the results of radiation therapy by implementing the following mechanisms:

- direct cytotoxic effect leads to a decrease in the volume of tumor tissue, and, therefore, is able to increase the effectiveness of radiation therapy;

- restoration of patency of the bronchial tree reduces the risk of purulent-inflammatory complications in the lung, including during radiation therapy;

- restoration of pneumatization of the lung tissue leads to the restoration of microcirculation. In general, both processes reduce post-radiation fibrotic changes;

- reducing the effect of debilitating symptoms such as shortness of breath, coughing and hemoptysis, facilitates the patient’s condition, and in some cases opens up the possibility for further treatment (transfer from incurable state to curative);

- PDT makes it possible to more accurately form radiation fields during dosimetric planning after restoration of anatomical structures.

The essence of the invention, including photodynamic therapy (FTD) on the intrabronchial / intratracheal component of the tumor with the introduction of the photosensitizer "Photolon" at a dose of 1.1 to 1.4 mg / kg of patient’s body weight, intravenously, drip for 30-40 minutes. Then carry out a session of laser irradiation of the tumor 3 hours after completion of the introduction of the photosensitizer. Light energy from 200 to 300 J / cm2 is supplied to the tumor during one irradiation session, depending on the clinical and morphological form of the tumor process. After PDT, cytostatic chemotherapy is carried out according to the schemes of Cisplatin 120 mg on the first day and Etoposide 200 mg on 1, 2, 3 days or Carboplatin 600 mg on the first day and Etoposide 200 mg on 1, 2, 3 days. The treatment cycle is repeated 2-3 times with an interval of 21 to 28 days. After chemotherapy is completed, remote radiation therapy is carried out with a single focal dose of 2 or 2.4 Gy to a total focal dose of 60 or 70 Gy.

Enumeration of figures.

FIG. 1. Survey radiograph of patient R. before treatment. Central cancer of the left lung: 1 - right lung of normal airiness; 2 - total atelectasis of the left lung.

FIG. 2. Survey radiograph of patient R. after treatment. Central cancer of the left lung: 1 - right lung of normal airiness; 2 - restoration of the left lung.

FIG. 3. Endophoto of patient C. before treatment. Central cancer of the left lung: 1 - right main bronchus; 2 - tumor obstruction of the left main bronchus.

FIG. 4. Endophoto of patient C. after treatment. Central cancer of the left lung: 1 - right main bronchus; 2 - restoration of the lumen of the left main bronchus.

The order of implementation of the method.

Patients are preliminarily injected with Photolon photosensitizer (PS) (a complex of sodium chloride of chlorin E6 and low molecular weight medical polyvinylpyrrolidone, developed by JSC Belmedpreparaty, registration certificate of the Ministry of Health of the Russian Federation P No. 015948/01 dated 02.12.2009) at a dose of 1.1 to 1.4 mg / kg of patient body weight. The calculated dose of "Photolon" is dissolved in 100-200 ml of 0.9% sodium chloride solution and injected intravenously for 30-40 minutes. After the administration of the Photolon FS, patients observe the light regime for 2-3 days to exclude manifestations of skin phototoxicity. A local tumor irradiation session is carried out 3 hours after the photosensitizer is introduced, laser therapeutic devices are used as a laser light source, generating radiation with a wavelength corresponding to the absorption spectrum of the Photolon photosensitizer (662 nm), the output radiation power is 1.2-1, 6 watts Laser light is delivered to the tumor tissue using flexible monofilament end fibers and microlenses during bronchoscopy through the working channel of the bronchoscope. Light energy of 200-300 J / cm2 is supplied to the tumors during one irradiation session from one or several fields, depending on the clinical and morphological form of the tumor process. After PDT, chemotherapy is carried out according to the schemes Cisplatin 120 mg on the first day and Etoposide 200 mg on 1, 2, 3 days or Carboplatin 600 mg on the first day and Etoposide 200 mg on 1, 2, 3 days. The treatment cycles are repeated 2-3 times. Then patients undergo radiation therapy in a single focal dose of 2 or 2.4 Gy to a total focal dose of 60 or 70 Gy. Treatment regimen

Examples of the method.

Example 1

Patient K., 64 years old, was admitted to the department 09/27/2013 with a diagnosis of Central cancer of the upper lobe of the right lung with passage to the main bronchus and trachea. T4N2M0. St. IIIB (histological conclusion September 16, 2013 - invasive squamous non-keratinized cancer). The patient complained of severe shortness of breath, cough. ECOG-1 status. According to the results of the examination: fibrobronchoscopy (09/09/2013) - a tumor comes out from the mouth of the right main bronchus, protruding into the lumen of the lower third of the trachea; the picture is deformed, infiltrated. According to computed tomography (08.21.2013) - a picture of central cancer of the upper lobe of the right lung with germination in the mediastinum and right main bronchus. The diagnosis was verified by tumor biopsy during bronchoscopy.

At the first stage of the combined treatment, on 03.10.2013, the patient underwent photodynamic therapy with the Photolon photosensitizer (100 mg per 100 ml of saline solution). 3 hours after drug administration, laser exposure was performed with the following parameters: Latus-2 laser apparatus, P - 1.3 W, treatment time 9 min. After the procedure, the phenomena of tissue edema were noted. 10/07/2013, the first course of chemotherapy was carried out by intravenous administration of cisplatin at a dose of 120 mg and etoposide at a dose of 200 mg on day 1 of the cycle, and 200 mg of etoposide intravenously on days 2 and 3 of the cycle. During the control bronchoscopy after 7 days, a positive dynamics was noted in the form of necrotic changes in the tumor and a decrease in its size. On November 7, 2013, repeated photodynamic therapy was carried out with the same parameters, a chemotherapy course was conducted from November 11, 2013 to November 13, 2013 according to the scheme used earlier. 12/05/2013, the third session of photodynamic therapy was conducted, a course of chemotherapy from 12/06/2013 to 12/08/2013. Clinically, a significant decrease in the severity of shortness of breath and cough was noted. According to the radiography of the patient revealed an improvement in pneumatization of the upper lobe of the right lung. With fibrobronchoscopy - a pronounced regression of the tumor component. When assessing the function of external respiration, an increase in the vital capacity of the lungs by 28% from the initial one was revealed. ECOG-0 status. From January 23, 2014 to March 13, 2014, the patient underwent a radical course of radiation therapy at the ElektaSynergy S accelerator (energy 10 MV) in a single focal dose of 2 Gy to SOD 70 Gy. When bronchoscopy October 10, 2014 - no signs of tumor growth were detected. With SKT of the chest organs 09/10/2014, 03/31/2015, 10/20/2015. severe regression of the tumor, no signs of tumor growth. The observation period for the patient is 30 months.

Example 2

Patient D., 59 years old, was admitted to the department on 08.25.2015 with a diagnosis of Central cancer of the right lung with passage to the trachea. T4N2M0. St. IIIB. (histological conclusion of 08/17/2015: glandular cancer, activating mutations of EGFR not detected). The patient complained of shortness of breath during physical exertion, dry cough. ECOG-1. According to the results of the examination: fibrobronchoscopy (August 27, 2015) - the mouth of the right main bronchus is closed by a tumor spreading to the trachea for 2.5 cm. According to computed tomography - a picture of central cancer of the right lung with lesion of the trachea and ventilation disorders in the upper lobe of the right lung. The diagnosis was verified by tumor biopsy during bronchoscopy.

At the first stage of combined treatment, on August 29, 2015, the patient underwent photodynamic therapy with the Photolon photosensitizer (100 mg per 100 ml of saline solution). 3 hours after drug administration, laser exposure was performed with the following parameters: Latus-2 laser apparatus, P - 1.3 W, treatment time 10 min. After the procedure, hemorrhagic necrosis was noted. On September 2, 2015, the first course of chemotherapy was carried out by intravenous administration of carboplatin at a dose of 600 mg and etoposide at a dose of 200 mg on day 1 of the cycle, and 200 mg of etoposide intravenously on days 2 and 3 of the cycle. During control bronchoscopy, a positive dynamics was observed in the form of necrotic changes in the tumor and a decrease in its size. On October 19, 2015, repeated photodynamic therapy was carried out with the same parameters, a chemotherapy course was conducted from October 21, 2015 to October 23, 2015 according to the previously used scheme. Clinically, there was a significant decrease in the severity of shortness of breath and cough. According to radiography, the patient noted an improvement in pneumatization of the upper lobe of the right lung. With fibrobronchoscopy - a pronounced regression of the tumor component. ECOG-0. From November 30, 2015 to December 31, 2015, the patient underwent a radical course of radiation therapy on the accelerator SL 75 (energy 6 MV) with a single focal dose of 2.4 Gy to SOD 60 Gy. The patient was discharged in satisfactory condition. Subsequently, it is observed in the control period 1 time in 3 months. Data on disease progression and relapse have not been obtained.

Confirmation of the achievement of a technical result.

The proposed method of treatment has been tested in patients with lung cancer. After the first stage of treatment (multi-course photodynamic therapy and chemotherapy), everyone achieved symptomatic improvement: decreased cough, shortness of breath; reduction of tumor size according to computed tomography; elimination of tumor stenosis of the bronchi. An objective treatment effect was observed in all patients: complete regression in 2 patients, partial regression in 2 patients. Of the complications, I-II degree leukopenia was noted in 2 patients, which did not require medical correction and an increase in the interval between treatment cycles, one patient developed endobronchitis with symptoms of increased cough and hyperthermia up to 38.5 ^o C, antibacterial therapy was carried out with the effect. At the second stage of treatment, all patients underwent the planned radical courses of radiation therapy up to SOD 60 and / or SOD 70 Gy. No significant complications of radiation therapy were identified.

The high clinical effectiveness of the method and the possibility of improving the results of the treatment of inoperable lung cancer with obstructive ventilation disorders are shown. The method allows to reduce the tumor mass, restore airway patency, reduce the symptomatic manifestation of the disease, improve local control, immediate and long-term treatment results.

Claims (1)

A method of treating lung cancer, including endoscopic photodynamic therapy by administering an intravenous drip of the photosensitizer for 30 to 40 minutes, followed by a laser session of the intrabronchial / intratracheal component of the tumor 3 hours after administration of the photosensitizer, characterized in that Photolon is administered as a photosensitizer at a dose of 1.1 to 1.4 mg / kg of patient’s body weight, after PDT, cytostatic chemotherapy is performed according to the Cisplatin 120 mg regimens on the first day and Etoposide 200 mg a 1, 2, 3 days or Carboplatin 600 mg on the first day and Etoposide 200 mg on 1, 2, 3 days, while the treatment cycle is repeated 2-3 times with an interval of 21 to 28 days, then remote radiation therapy is carried out in a single focal dose of 2 Gy or 2.4 Gy to a total focal dose of up to 60 or 70 Gy.

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