RU2286817C2 - Method for combined therapy of locally metastasing malignant tumors of trachea and/or bronchi - Google Patents

Abstract

FIELD: medicine, oncology.

SUBSTANCE: one should carry out argon-plasmatic luminal recanalization of trachea and/or bronchi, at power being about 60-90 W followed by conducting brachytherapy at the length of sensor's movement trajectory of about 5-20 cm, at pace of 5 mm and depth of reference isodosage being 10 mm against the sensor. It is necessary to provide applicator's movement being 1-3 cm above and below the tumor at applying the dosage ranged 14-28 Gy once daily per 7 Gy. Then one should fulfill distance radiation therapy 5 times weekly per 1-2 Gy up to TFD being 45-55 Gy. Additionally, before the onset of radiation therapy one should carry out photodynamic therapy with "Photoditasin" preparation at 0.8-1.5 mg/kg and radiation of semiconductor laser at wave length being 662 nm and total dosage of energy being 400 J. The innovation enables to achieve the decrease of tumoral mass, reconstruct the passability of respiratory tract and decrease intoxication and pain syndrome.

EFFECT: higher efficiency of therapy.

3 ex

Description

The invention relates to methods for treating cancer, namely malignant tumors of the trachea and central bronchi.

Malignant neoplasms remain the most acute medical and social problem. Oncological incidence is steadily increasing. In Russia, the contingent of patients with malignant neoplasms is more than 2 million people, i.e. 1.5% of the country's population. WHO experts believe that the upward trend in cancer incidence worldwide will continue, with up to 90% of patients with some localization of tumor processes being incurable. Of these, 70% need palliative care and, as a rule, do not receive it (Kudryavtsev D.V. et al. Superfractionation in radiation therapy of non-small cell lung cancer // Russian Oncological Journal. - 2003. - No. 2. - P.10- 14; Poddubny B.K., Davydov M.I. et al. Bronchoscopy in palliative treatment of patients with lung cancer // Vestnik RONTS. - 2003. - No. 1. - P.33-36).

Lung cancer is one of the first among the incidence rates of malignant neoplasms. In Russia, it is in second place in the overall structure of oncological diseases and in first (31%) among male cancers. Every year in Russia, more than 63,000 cases of RL are registered, and 60,000 people die from it. St. Petersburg also maintains one of the highest levels of cancer incidence. Thus, statistics indicate that lung cancer is one of the most common and usually has an unfavorable prognosis of cancer (McDuffie HH, Klaassen DJ, Dosman JA Female-Male differences in patients with primary lung cancer // Cancer 1987; 59; : 1825-1830; Martini N., Bains M., Burt M. et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer // J. Thorac. Cardiovasc. Surg. - 1995. - Vol. 109 .- P.120-129; Landis SH, Murray T., Bolden S., Wingo PA Cancer Statistics, 1999 // CA Cancer J Clin 1999; 49: 8-31).

In recent years, in medicine, there has been an awareness of the fact that functional parameters (in the broad sense of the term) are essential for evaluating the effectiveness of treatment methods and predicting the outcome of the disease. Among these, among these parameters, a special place is occupied by the quality of life. This term, recently born in Western philosophy, has already taken a significant place in sociology and medicine (G. Novikov et al. Prospects for the development and improvement of palliative care for cancer patients in Russia // Russian Medical Journal, 1995, No. 1, - C. 13-17; Merabishvili V.M. Malignant neoplasms in St. Petersburg in 1996 - St. Petersburg, 1999. - 219 p .; Chissov V.I., Novikov G.A., Prokhorov B.M. Palliative care - one of the priority areas of national oncology // III Congress "Palliative medicine and rehabilitation in healthcare “. Palliative medicine and rehabilitation, 2000, No. 1-2, - C.6).

The severity of the condition of inoperable cancer patients and correspondingly low quality of life are often caused by impaired patency of the central bronchi and trachea, and then the question arises of the need for their recanalization to increase the respiratory surface, eliminate the phenomena of obstructive pneumonia and to obtain the possibility of an antitumor treatment that prevents or slows down the onset of relapse. The proactive effect on the tumor that prevents obstruction of the bronchi is also relevant (Novikov G.A., Starinsky V.V. et al. Prospects for the development of palliative care for cancer patients in Russia // Actual issues of oncology: Mater, Int. Sympos., 1996, St. Petersburg ., May 14-17, 1996, pp. 215-216; Asakhin S.M., Zolotkov A.G., et al. Radiation reactions and complications in palliative radiation therapy of patients with lung cancer // IV Conference “Palliative care in oncology ", April, 1999, Antalya, Palliative medicine and rehabilitation, No. 3, 1999, p. 35; Trakhtenberg A.Kh., Chiss OV V.I. Clinical Oncopulmonology // Moscow. - 2000. - 599 p.). The results of the use of chemoradiotherapy in this group of patients remain unsatisfactory. Attempts to improve the immediate results of treatment by improving the options for remote radiation exposure have been ineffective, since the increase in dose loading is limited by the tolerance of the surrounding healthy tissues and organs. Under these conditions, the advantages of intracavitary (contact) irradiation, which provides a significantly larger focal dose in the tumor than in adjacent tissues, become apparent. With the introduction into clinical practice of modern devices for brachytherapy with a walking radiation source, there are certain hopes for increasing the effectiveness of palliative treatment. The contingent of patients that can be subjected to intracavitary radiation therapy is limited, due to obturation, or a sharp narrowing of the lumen of the central bronchi, or trachea, which makes it impossible to deliver the applicator with a radioactive source to the tumor (Trakhtenberg A.Kh. Lung cancer. - M .: Medicine . - 1987. - 304 p .; Sokh JD, Byhardt RW, Komaki R. The Role of Radiotherapy in Squamous, Large Cell and Adenocarcinoma of the lung // Seminars Oncol. - 1983 - Vol.1. - P.81-94 ; Sorensen JB Prognosis and prognostic factors in adenocarcinoma of the lung. // Dan. Med. Bull. - 1992. - Vol.5. - P.453-463; Feldman ER, Eagan RT, Schaid DJ. Metastatic bronchioloalveolar carcinoma and metastatic adenocarcinoma of the lung: co mparison of clinical manifestations, chemotherapeutic responses, and prognosis. // Mayo Clinic. Proc. - 1992. - Vol.67. - P.27-32). An analysis of the literature data showed the novelty of the “Method for the treatment of locally advanced malignant tumors of the central bronchi and / or trachea”.

Closest to the proposed method are the previously proposed methods for combining laser recanalization of the airway lumen with photodynamic therapy (Sokolov V.V., Filonenko E.V., Sukhin D.G. Prolonged photodynamic therapy of incurable cancer patients // V Conference "Palliative care in oncology ", April, 2001, Bodrum, Palliative medicine and rehabilitation, No. 2-3, 2001, - С.25; Stranadko EF, Filkova EM, Meshkov VM A new version of the photodynamic therapy of locally advanced malignant neoplasms ovanii // New technologies in clinical practice: Collection of scientific papers on the materials of the scientific-practical conference on the 85th anniversary of the Central Clinical Hospital named after N.A.Semashko, Moscow, 1999. - M., 1999. - P.70-72; Zaporozhan V.N., Grubnik V.V., Poddubny B.K. Lasers in endoscopy. Odessa: Medical State University, 1997. - 220 p.). The advantages of these techniques are supplemented by the effects of argon plasma electrocoagulation, brachytherapy and remote radiation therapy, as well as the pharmacodynamics of the new effective photosensitizer “photoditazine” used in conducting photodynamic therapy, which allows to achieve maximum cytoreduction and optimal restoration of the lumen of the trachea and / or bronchi before the start of radiation therapy.

The technical result of the method is 1) a decrease in tumor mass (cytoreduction), 2) restoration of airway patency, 3) reduction of intoxication and pain. This is achieved by performing argon plasma recanalization of the trachea and / or bronchi (ERBE ARC-300 apparatus, registration number 98/1735 dated 12/28/98. Certificate No. 4418755) followed by photodynamic therapy, followed by brachytherapy and external radiation therapy.

At the clinic of the Research Institute of Oncology named after prof. N.N. Petrova used a functional complex consisting of a unit for monitoring and controlling argon power, a high-frequency generator, and flexible electrode probes. In the functional complex there was software with the ability to select the optimal parameters of the generator power and argon flow rate, allowing precise control of the depth and volume of the impact. Argon plasma coagulation is a method of monopolar high-frequency electrosurgery, in which the energy of a high-frequency current is transmitted to the tissue in a non-contact manner by means of ionized argon. An argon plasma arc is formed between the electrode and the tissue site that has the least resistance. The resulting dehydration (desiccation) of the coagulated tissue increases its resistance, which leads to the displacement of the argon arc to the tissue site with less resistance, ensuring the homogeneity of the coagulation zone and the controllability of the exposure depth. The coagulation depth, depending on the power and duration of application of the electrode does not exceed 3 mm, reducing the risk of perforation. Typically, coagulation was carried out at a power of 60-90 W (average 70 W) with an argon flow rate of 2.0-2.4 l / min (average 2.2 l / min). One of the advantages of the method is coagulation in an oxygen-free medium, which allows you to affect the tissue without significant carbonization (carbonization).

For carrying out photodynamic therapy, the photoditazine photosensitizer (registration No. 249188) was used based on the water-soluble form of chlorin E6, which has a number of biological, physicochemical, and energy characteristics that distinguish it from previously used photosensitizers in the clinic, such as: 1) powerful absorption band in the red long wavelength region of the spectrum (662 nm); 2) rapid pharmacodynamics (accumulation time in the tumor - 2 hours, the time of complete elimination from the body - 24-36 hours); 3) high amphiphilicity (accumulation coefficient in the tumor compared to normal tissue 10: 1-15: 1); 4) low dark phototoxicity, providing ease of use in clinical and outpatient settings; 5) high light photocytotoxicity associated with the active generation of singlet oxygen (75-96%) when interacting with laser radiation; 6) high penetration in tissue, since the wavelength of the laser radiation lies in the region of their optical transparency; 7) a large therapeutic breadth of the drug; 8) low allergenicity. Irradiation was carried out with an Atkus-2 semiconductor laser (registration No. 29/05010104 / 5958-04 of the Ministry of Health of the Russian Federation dated January 26, 04; certificate of conformity ROS RU.IM 15.V.00404) with a power density of 300 mW / cm ² ; the total radiation power was 400 J. The dose of the drug ranged from 0.8 to 1.5 mg / kg of body weight. The tumor was irradiated 2 hours after drug administration. In addition to wearing sunglasses during the day, no other protective measures were required. The administration of photoditazine followed by laser irradiation did not cause widespread phototoxic endotracheobronchitis. Hyperemia of the mucosa was observed in a rather limited area adjacent to the "exposure zone". In no case was the cumulation of effect observed.

Intraluminal brachytherapy was performed on a Microselectron HDR apparatus (Nucleotron) with a source of iridium-192, a high radiation dose rate with an activity of 5-10 curies. The movement of the source was carried out with a step of 5 mm. The length of the path of the source is from 5 to 20 cm, the depth of the reference isodose is 10 mm from the source. For endocuritherapy, a standard applicator was used, which is installed under local anesthesia through the instrument channel of the fibrobronchoscope in such a way as to ensure the movement of the source to a distance including the tumor or wall of the bronchus and trachea above and below the tumor from 1 to 3 cm. When irradiating, the principles of conformal radiotherapy were implemented in order to which is bringing the maximum possible dose of radiation to the tumor and reducing the dose load in the region of adjacent organs and tissues, which reduces the frequency of radiation damage in the treatment of primary neoplasm. Remote radiation therapy was carried out on the apparatus LUEV-15M1 up to SOD 45-55 Gy.

The study included data on 15 patients who, from April 2001 to June 2003, performed a total of 23 sessions of argon plasma electrocoagulation in our clinic, followed by brachytherapy and external radiation therapy. In 7 patients there was a tumor lesion of one of the lobar bronchi with a transition to the main, in 4 - a lesion of the main bronchus with a transition to the trachea and in 4 a lesion of one of the lobar bronchi. The morphological structure of the tumors was as follows: 9 patients had squamous cell carcinoma, and 6 patients had adenocarcinomas.

Full recanalization was achieved in 10 (66.7%) patients and partial in 5 (33.3%) - with significant peribronchial or peritracheal components. In all patients, the intervention was performed with a palliative purpose. Immediately after the recanalization, patients noted a subjective improvement in well-being, which was confirmed by objective data - physical examination, improvement of clinical, biochemical and gas blood counts, and radiological data.

Brachytherapy as the 2nd stage of treatment was carried out in the period from 1 to 3 weeks after recanalization. This time was necessary for the subsidence of reactive inflammation, scab discharge and rejection of necrotic parts of the tumor. The dose was adjusted from 14 to 28 Gy in a regimen of 1 time per week for 7 Gy.

Remote radiation therapy, as the 3rd stage of treatment was carried out immediately after brachytherapy in the regime of 5 times a week, 1-2 Gy to SOD 45-50

Of the 15 treated patients, up to 12 months, the need for repeated argon plasma recanalization did not arise in any patient, and in the period 12 to 18 months - in 4 patients. To date, 6 patients have died from generalization of the process. At the dispensary observation, 9 patients remain.

The inventive step of the proposed method is confirmed by the fact that in all cases (66.7%), or partially (33.3%), the patency of the bronchi and trachea was restored, an improvement in the function of external respiration, a decrease in intoxication and pain syndrome were noted. The average duration of the relapse-free period with full clinical remission was 28 months (12-33 months), and with partial remission - 15 months (from 8 to 23 months), while with laser recanalization, the duration of the relapse-free period is on average 11 months, with standard high-frequency electrocoagulation - 9 months, and with chemoradiotherapy - 7 months.

As clinical examples and to confirm the condition of "industrial applicability" we present the following clinical observations.

Example 1. Patient P.M.V., 39 years old. Complaints upon receipt of a temperature increase to 39-40 ° C; shortness of breath with moderate physical exertion, weakness, cough with purulent sputum. Clinical diagnosis: cancer of the right upper lobar bronchus with a transition to the main and trachea. Morphological examination (bronchobiopsy) - squamous cell carcinoma. Operation 12.03.2001, argon plasma coagulation of the tumor, partial recanalization achieved. The duration of the operation is 25 minutes. March 22 and 29, 2001 - two sessions of photodynamic therapy (photoditazine - 1.5 mg / kg; total irradiation power - 400 J at a power density of 300 mW / cm ² ). April 12 and 29, 2001, brachytherapy up to SOD 14 Gy. Remote radiation therapy 05/07/2001 - 06/03/2001 to SOD 48 Gy. With dynamic clinical, radiological and endoscopic observation, remission is 17 months.

Example 2. Patient G.Sh.P., 72 years old. Complaints upon admission for shortness of breath with slight physical exertion, weakness, fever up to 38-39 ° C, hemoptysis. Clinical diagnosis: Cancer of the right lower lobe bronchus with a transition to the upper lobe and main. In a morphological study (bronchobiopsy) - highly differentiated adenocarcinoma. Operation 02.22.2002, argon plasma coagulation of the tumor, partial recanalization achieved. The duration of the operation is 10 minutes. 03/17/2002 - a session of photodynamic therapy (photoditazine - 1.5 mg / kg; total radiation power - 400 J at a power density of 300 mW / cm ² ). April 13-20, 2002 brachytherapy up to SOD 21 Gy. Remote radiation therapy 05/25/2002 - 07/10/2002 to SOD 45 Gy. During dynamic clinical, radiological and endoscopic observation, partial remission of 9 months (to date).

Example 3. Patient D.S.L., 58 years old. Complaints upon admission for shortness of breath with slight physical exertion, weakness, fever up to 38 ° C, hemoptysis. Clinical diagnosis: Cancer of the left main bronchus with metastases in the mediastinal lymph nodes. Morphological examination (bronchobiopsy) - adenocarcinoma. Operation 06/28/2003, argon plasma coagulation of the tumor, achieved complete recanalization. The duration of the operation is 35 minutes. July 15, 2003 - two sessions of photodynamic therapy (photoditazine - 1.0 mg / kg; total irradiation power - 400 J at a power density of 300 mW / cm ² ). 07-30.07.2003, brachytherapy to SOD 21 Gy. Remote radiation therapy 08/12/2003 - 09/17/2003 to SOD 50 Gy. With dynamic clinical, radiological and endoscopic observation, complete remission of 12 months.

Claims (1)

A method for the combined treatment of locally advanced malignant tumors of the trachea and / or bronchi, including argon plasma recanalization of the lumen of the trachea and / or bronchi, at a power of 60-90 W, followed by brachytherapy with a source path length of 5-20 cm, a step of 5 mm and a depth reference isodose 10 mm from the source; with the provision of the movement of the applicator above and below the tumor from 1 to 3 cm and summing up the dose from 14 Gy 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 doses of 45-55 Gy, characterized in that, in addition, before the start of radiation therapy, photodynamic therapy with the drug "photoditazine" 0.8-1.5 mg / kg and radiation of a semiconductor laser with a wavelength of 662 nm and a total dose of energy of 400 J.