RU2358775C1 - Integrated treatment of malignant tumour pleura involvement accompanied with exudative pleurisy - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: integrated treatment of malignant tumour pleura involvement accompanied with exudative pleurisy is ensured with argon-plasma electrocoagulation of pleura at power 60-90 Wt and argon consumption 2.0-2.4 l/min followed with intraoperative photodynamic therapy. A photosensitiser is Photoditasine dosed 1.5 mg/kg. The irradiation involves diode laser of wavelength 662 nm and power density 300 mWt/cm², at total energy dose 400 J/cm². In addition, it is combined with hyperthermic intrapleural chemoperfsion of cisplatin 100 mg in 1500-3000 ml of 0.9 % sodium chloride solution at temperature 42°C within 60 minutes at feed rate 1200 ml/min.

EFFECT: reduced tumour weight, terminated exudation and protein loss, reduced inflammation, intoxication and pain syndrome, local and systemic cytostatic action of cisplatin.

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Description

Malignant neoplasms remain the most acute medical and social problem. In the structure of mortality in the Russian population, malignant neoplasms occupy the third place and make up 13%. The contingent of patients with malignant neoplasms is more than 2 million people, i.e. 1.4% of the country's population. WHO experts believe that the upward trend in cancer incidence will continue, with up to 90% of patients with some localization of tumor processes being incurable. In Russia, more than 300 thousand patients die every year from malignant neoplasms, of which 70% need palliative treatment. The remaining unsolved problem of early diagnosis of lung cancer leads to the fact that the bulk of patients (more than 75%) go to specialized medical institutions in stages III-IV of the disease. In this regard, the provision of palliative care to patients with common forms of malignant neoplasms is becoming one of the main problems of oncological services in most developed countries of the world (Davydov M.I., Volkov S.M., Polotsky B.E. Improving the surgical treatment of patients with non-small cell lung cancer / / Russian Journal of Oncology Journal - 2001. - No. 5. - P.14-17; Novikov G.A., Osipova N.A., Starinsky V.V., Prokhorov B.M., Benenson L.I. , Gazizov AA Prospects for the development and improvement of palliative care for cancer patients in Russia // Rossi Medical Journal of Medicine, 1995, No. 1, pp. 13-17; Trakhtenberg A.Kh., Chissov V.I. Clinical Oncopulmonology // M. - 2000. - 599 p .; Hansen N.N., Bunn R.A. Lung cancer therapy // Taylor & Francis. 2005. - P.100-105).

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 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 the world, Russia, St. Petersburg. - SPb., IPK BIONT LLC, 2007. - 422 s; Chissov V.I., Novikov G.A., Prokhorov B .M. Palliative care is one of the priority areas of Russian oncology // III Congress “Palliative medicine and ilitatsiya in health care ", Palliative Medicine and Rehabilitation 2000, №1-2, - C.6).

The severity of the condition of inoperable cancer patients and correspondingly low quality of life are often caused by the presence of exudative pleurisy, and then the question arises of the need to eliminate it to increase the respiratory surface, eliminate compression of the lung and mediastinal organs, the phenomena of obstructive pneumonia, and often to get the opportunity to continue conducting special antitumor treatment.

Lung cancer is the main cause of malignant exudative pleurisy. It occupies one of the first places 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. More than 63,000 cases of lung cancer are registered annually in Russia, and 60,000 people die from it. St. Petersburg also maintains one of the highest levels of cancer incidence. Statistics show that lung cancer is one of the most common and is usually characterized by an unfavorable prognosis of cancer. According to various sources, the bulk of patients (more than 75%) go to specialized medical institutions in stages III-IV of the disease. In more than 50% of these patients, the disease is accompanied by respiratory failure due to the presence of exudative pleurisy (V. Merabishvili. Malignant neoplasms in the world, Russia, St. Petersburg. - SPb., IPK BIONT LLC, 2007. - 419-422 sec. .; Landis SH et al. Cancer Statistics, 1999 // CA Cancer J Clin 1999; 49: 8-31; Ling C.C. et al. High-tech will improve radiotherapy of nsclc: a hypothesis waiting to be validated // Int. J. Radiat. Oncol. Biol. Phys. - 2004. - Vol. 60. - P.3-7; Waller D, Peake MD, Stephens RJ, et al. Chemotherapy for patients with non-small cell lung cancer. The surgical setting of the Big Lung Trial. Eur J CardioThorac Surg. 2004; 26: 173-182). In addition to lung cancer, secondary carcinomatous exudative pleurisy can occur in common cancers of the breast (45-50%), stomach (30-65%), thyroid gland (25-45%) and some other malignant neoplasms. About 2% of the total number of specific pleural effusions account for diffuse malignant pleural mesothelioma (Kolesnikov I.S., Lytkin M.I. Surgery of the lungs and pleura // L .: Medicine, 1988. - 382 p .; Malcolm. Et al. The Role of Surgery in N2 Non-Small Cell Lung Cancer. Clin. Cancer Res. 2005; 11 (13 Suppl) 5033-5037; Rodriguez-Panadero F. // Monaldi Arch. Chest Dis. - 2000 Feb. - Vol. 55 (1). - P.17-19; Schiller JH et al. Comparison of outcome and patients characteristics in advanced NSCLC: analysis of ECOG 1980-2000 // Proc. ASCO. - 2002. - Vol.21. - P. 304f ) Exudative pleurisy, or hydrothorax, is the result of an increase in capillary permeability as a result of tumor infiltration of the pleura, inflammation, radiation, etc. The characteristic signs of pleural effusion are a decrease in excursions of the chest and respiratory volume, pronounced shortness of breath and pain. To prevent exudation, methods such as surgical (open and endoscopic) pleurectomy, chemical pleurodesis (intrapleural administration of acrychine, talc, tetracycline, delagil), physical pleurodesis (electrocoagulation, argon plasma, laser, cryodestruction) are traditionally used. Intrapleural administration of chemotherapeutic drugs such as cyclophosphamide, bleomycetin, etc. is widespread. However, the results of using these methods cannot be considered satisfactory. Physical and chemical pleurodesis usually allow only a partial effect due to the frequent limited obliteration of the pleural cavity, as well as the inaccessibility of many of its departments for manipulation. The high probability of resistance of pleural effusions to intracavitary administration of chemotherapy (in 43-82% of cases) is also a frequent cause of the repeated accumulation of abundant pleural effusion. In the foreign literature of recent years, there are reports of the use of intrapleural chemoperfusion (intrathoracic chemohyperthermia - ITCH) with cisplatin and / or mitomycin. However, the use of this method in isolation did not allow the authors to achieve a significant improvement in immediate and long-term results (recurrence of fluid accumulation of more than 4%; median survival of less than 5 months) with a significant number of complications (up to 30%) (Monneuse O. et al. Long-term results of intrathoracic chemohypertermia (ITCH) for the treatment of pleural malignancies // British J. of Cancer. - 2003; Vol.88. - P.1839-1843; De Bree E. et al. Cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy in patients with malignant pleural mesothelioma or pleural metastases of thymoma. // Chest. - 2002. - 121: 480-487; Yellin A. et al. Hyperthermic pleural perfusion with cisplatin: early clinical experience. Cancer. - 2001. - 92: 2197- 22 03).

In general, according to the literature, the use of the above-described isolated methods allows to completely stop the accumulation of effusion in the pleural cavity in no more than 70-80% (Akopov A.A., Kondratiev V.B. Intracavitary use of bleomycetin in case of tumor pleurisy // Materials 3rd Russian Oncological Conference. St. Petersburg, - 1999. P.137-138; Moiseenko VM Modern chemotherapy of disseminated breast cancer // Materials of the 3rd Russian Oncological Conference. St. Petersburg, - 1999. P.103-110 ; Hansen N.N., Bunn R.A. Lung cancer therapy // Taylor & Fran cis. 2005. - P.100-105; Sahn SA Pulmonary Emergencies // Churchill Livingstone, New York, 1982, p. 295-299; Raftopoulas H. et al. Assessing the role of chemotherapy in advanced NSCLC: a comprehensive review of large, randomized trial 1991-2001 // Proc. ASCO. - 2002. - Vol.21. - P.322a). One cannot ignore the large number of side effects and complications in the implementation of these techniques, such as allergic reactions, respiratory distress syndrome, the possibility of developing systemic and multiple organ failure (Campos JR et al. Thoracoscopic pleurodesis of talcum powder // Chest. - 2001 Mar. - Vol .119 (3) .- P.801-806; Furedi A. et al. Videothoracoscopic pleurodesis in the treatment of malignant pleurisy // Acta Chir Hung. - 1999. - No. 2. - Vol.55. - P.17-19; Hansen HH, Bunn PA Lung cancer therapy // Taylor & Francis. 2005. - P. 100-105; Rodriguez-Panadero F. // Monaldi Arch. Chest Dis. - 2000 Feb. - Vol. 55 (1). - P.17 -19).

Under these conditions, the advantages of introducing combined and complex methods for eliminating hydrothorax in malignant exudative pleurisy, which make it possible to eliminate these drawbacks by complementing the effects, become apparent. An analysis of the literature data showed the novelty of the "Method for the complex treatment of malignant tumor lesions of the pleura, accompanied by exudative pleurisy."

Closest to the proposed method are the previously proposed method, which consists in conducting argon plasma electrocoagulation of the pleura followed by intraoperative photodynamic therapy with a photoditazine photosensitizer and radiation of a 662-nm semiconductor laser, with the aim of reducing tumor mass, reducing exudation and protein loss, and reducing inflammation , intoxication and pain (patent No. 2289352, publ. December 20, 2006, bulletin No. 35).

The advantages of a combination of argon plasma electrocoagulation of pleura with photodynamic therapy are supplemented by effects due to hyperthermic intrapleural chemoperfusion with cisplatin, which allows for maximum cytoreduction, cessation of exudation and protein loss, cessation of inflammation, tumor intoxication and pain due to local and systemic effects.

The technical result of the method is 1) a decrease in the tumor mass (cytoreduction); 2) termination of exudation and loss of protein; 3) reduction of inflammation, intoxication and pain; 4) local and systemic cytostatic effects of cisplatin. This is achieved by carrying out argon plasma electrocoagulation of the pleura (ERBOTOM ICC-300; ARS-300; ICC ERBE VIO - ERBE Elektromedizin, Germany), followed by intraoperative photodynamic therapy and hyperthermic intrapleural chemoperfusion (perfusion perfusion pump) , TsNIIRTK, Russia; perfusion physiological block oxygenator MINIMAX, Medtronic, USA).

The clinic of the Federal State Institution of Oncology Research Institute named after N.N. Petrov of Roszdrav used a functional complex consisting of an argon supply monitoring and control unit, 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 damage to the main vessels and organs of the chest cavity. Coagulation is carried out at a power of 60-90 W, with an argon flow rate of 2.0-2.4 l / min. One of the advantages of the method is coagulation in an oxygen-free environment, which allows you to affect the tissue without significant carbonization (carbonization) and smoke of the pleural cavity.

For photodynamic therapy, the photoditazine photosensitizer (registration number 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 band absorption 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. The irradiation was carried out with an Atkus-2 semiconductor laser (registration number No. 29/05010104 / 5958-04 of the Ministry of Health of the Russian Federation dated January 26, 2004; certificate of conformity ROS RU.IM15.V.00404) with a power density of 300 mW / cm ² ; the total radiation power was 400 J. The dose of the drug was 1.5 mg / kg of body weight. The tumor was irradiated 2 hours after drug administration (the drug was administered before surgery). In addition to wearing sunglasses during the day, no other protective measures were required. Administration of photoditazine followed by laser irradiation did not cause common phototoxic reactions. In no case was the cumulation of effect observed.

When carrying out hyperthermic intrapleural chemoperfusion (MARS perfusion pump, TsNIIRTK, Russia; MINIMAKS Medtronic, USA perfusion physiological block oxygenator), the cytostatic drug cisplatin was used, bifunctionally alkylating DNA, suppressing 100 mg nucleic acid biosynthesis, in 1500-3000 ml of 0.9% sodium chloride solution. Hyperthermic intrapleural chemoperfusion was carried out through standard silicone drainage tubes supplied in the kit at a temperature of 42 ° C for 60 minutes with a solution flow rate of 1200 ml / min.

All stages of treatment were carried out sequentially during one surgical intervention under conditions of general anesthesia, one-lung ventilation in the anterolateral or lateral position of the patient with video thoracoscopy or open transthoracic surgery. At the end of the operation, passive pleural drainage was established to control hemostasis and exudate evacuation in the immediate postoperative period (from 1 to 3 days).

The study included data on 6 patients aged 35 to 63 years, 2 women and 4 men, who from April 2007 to February 2008 conducted complex treatment of malignant tumor lesions of the pleura accompanied by exudative pleurisy in our clinic . In all cases, morphological verification of the process was performed. The described method of treatment was applied in two patients with disseminated tumor in the pleura with advanced non-small cell lung cancer and in four patients with diffuse pleural malignant mesothelioma. All patients managed to achieve an immediate stable complete cessation of accumulation of effusion in the pleural cavity. The need for repeated surgical interventions and pleural punctures did not arise. In all patients, the intervention was performed with a palliative purpose. Immediately after the combined treatment, 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.

The inventive step of the proposed method is confirmed by the fact that in all cases immediately (100%; N = 6) the accumulation of pleural effusion was completely eliminated, an improvement in the function of external respiration, a decrease in intoxication and pain syndrome were noted. There were no cases of recurrence of malignant exudative pleurisy in patients.

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

Example 1. Patient V.M.A., 44 years old. Complaints upon receipt of intense chest pain on the left, shortness of breath with little physical exertion, weakness. Clinical diagnosis: malignant diffuse pleural mesothelioma on the left. Exudative pleurisy. Morphological examination (pleural biopsy) - epithelioid cell malignant mesothelioma. Operation 05/14/2007, videothoracoscopy on the left, argon plasma pleurodesis with intraoperative photodynamic therapy (photoditazine - 1.5 mg / kg; total irradiation power - 400 J / cm ² at a power density of 300 mW / cm ² ) and hyperthermic intrapleural chemoperfusion with cisplatin 100 mg in 3000 ml of 0.9% sodium chloride solution at a temperature of 42 ° C for 60 minutes with a solution flow rate of 1200 ml / min. The duration of the operation is 60 minutes. During dynamic clinical and radiological observation, the absence of recurrence of exudative pleurisy within 10 months (the entire observation period).

Example 2. Patient Z. L.S., 59 years old. Complaints of admission for shortness of breath during exertion, dry cough, chest pain, weakness. Clinical diagnosis: Malignant diffuse-nodular pleural mesothelioma on the right with intraorgan metastases. Exudative pleurisy. Morphological examination (pleural biopsy) - epithelioid cell malignant mesothelioma. Operation June 24, 2007. Right-sided thoracotomy, argon-plasma pleurodesis with intraoperative photodynamic therapy (photoditazine - 1.5 mg / kg; total irradiation power - 400 J / cm ² at a power density of 300 mW / cm ² ) and hyperthermic intrapleural chemoperfusion with cisplatin 100 mg in 1600 ml of 0.9% sodium chloride solution at a temperature of 42 ° C for 60 minutes with a solution flow rate of 1200 ml / min. The duration of the operation is 45 minutes. During dynamic clinical and radiological observation, the absence of recurrence of exudative pleurisy for 9 months (the entire observation period).

Example 3. Patient F.V.A., 35 years old. Complaints upon receipt of a fever up to 39 ° C; shortness of breath with slight physical exertion, weakness, cough with viscous sputum, hoarseness of the voice. Clinical diagnosis: Cancer of the right upper lobar bronchus with a transition to the main and metastases in the lymph nodes of the lung root and mediastinum. Dissemination of pleura. Exudative pleurisy. Morphological examination (pleural biopsy) - moderately differentiated adenocarcinoma. Surgery July 16, 2007, argon-plasma pleurodesis with intraoperative photodynamic therapy (photoditazine - 1.5 mg / kg; total irradiation power - 400 J / cm ² with a power density of 300 mW / cm ² ) and hyperthermic intrapleural chemoperfusion with cisplatin 100 mg in 2500 ml 0.9% sodium chloride solution at a temperature of 42 ° C for 60 minutes with a solution feed rate of 1200 ml / min. The duration of the operation is 55 minutes. During dynamic clinical and radiological observation, the absence of recurrence of exudative pleurisy is 8 months (the entire observation period).

Claims (1)

A method for the complex treatment of malignant neoplastic lesions of the pleura, accompanied by exudative pleurisy, including argon plasma electrocoagulation of the pleura at a power of 60-90 W and argon consumption of 2.0-2.4 l / min, followed by intraoperative photodynamic therapy with the drug "photoditazine" 1, 5 mg / kg and radiation of a semiconductor laser with a wavelength of 662 nm, with a power density
300 mW / cm ² and a total energy dose of 400 J / cm ² , characterized in that they additionally produce hyperthermic intrapleural chemoperfusion with cisplatin 100 mg in 1500-3000 ml of a 0.9% sodium chloride solution at a temperature of 42 ° C for 60 minutes with a solution feed rate of 1200 ml / min.