Integrated treatment of malignant tumour pleura involvement accompanied with exudative pleurisy

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.

3 ex

 

Malignant neoplasms remain acute medical and social problem. In the structure of mortality Russia malignant neoplasms ranked third and account for 13%. The majority of patients with malignant tumors is more than 2 million people, or 1.4% of the population of the country. Who experts believe that the trend towards growth in cancer incidence will continue, with up to 90% of patients some localizations neoplastic processes will be incurable. In Russia from cancer annually kills more than 300 thousand patients, 70% of them need palliative care. Remaining unresolved at present the problem of early diagnosis of lung cancer leads to the fact that the majority of patients (over 75%) is in specialized medical institutions in the III-IV stages of the disease. In this regard, the provision of palliative care to patients with common forms of malignant neoplasms is one of the major challenges for cancer services in most developed countries of the world (Davydov M.I., wolves S.M., Polotsk BE the Improvement of surgical treatment of patients with non-small cell lung cancer // ROS. on Oncology. Journe. - 2001. No. 5. - P.14-17; G.A. Novikov, Osipova N.A., starinsky CENTURIES, Prokhorov BM, Benenson LI, Gazizov AA Perspective what s the development and improvement of palliative care cancer patients in Russia // Russian medical journal, 1995, No. 1, - S-17; Trachtenberg AH, Chissov V.I. Clinical ecopolitology // M - 2000. - 599; Hansen N.N., Bunn R.A. Lung cancer therapy // Taylor&Francis. 2005. - P.100-105).

In recent years, medicine has been aware of the fact that the functional parameters (in the broad sense of the term) are important for evaluating the effectiveness of therapeutic techniques and predict disease outcome. Among these options is a special quality of life. This term, recently born in Western philosophy, has taken a significant place in sociology and medicine (G.A. Novikov et al. Prospects for the development and improvement of palliative care cancer patients in Russia // Russian medical journal, 1995, №1, - S-17; Merabishvili V.M. Malignancies in the world, Russia, St. Petersburg. - SPb., IPK BIONT", 2007. - 422; Chissov V.I., Novikov GA, Prokhorov BM Palliative care is one of prioritetnyh national Oncology // III Congress of Palliative medicine and rehabilitation in health care, Palliative medicine and rehabilitation, 2000, No. 1-2, - P.6).

The severity of the condition inoperable cancer patients and therefore a low quality of life, often due to their exudative pleurisy, and then the question arises about the need to eliminate to increase the respiratory surface, whether the eradicate compression of the lung and the mediastinum, effects of obstructive pneumonia, and often to be able to continue to conduct special cancer treatment.

Lung cancer is the main cause of malignant exudative pleurisy. He is one of the first places among the incidence of malignant neoplasms. In Russia he is in second place in the overall structure of oncological diseases and on the ground (31%) among malignant tumors in men. In Russia annually registers more than 63000 cases of lung cancer and dies from it to 60,000. In St. Petersburg also remains one of the highest levels of cancer incidence. Statistics show that lung cancer is one of the most common and is characterized by generally poor prognosis of cancer. According to various sources, the majority of patients (over 75%) is in specialized medical institutions in the III-IV stages of the disease. More than 50% of these patients the disease is accompanied by respiratory insufficiency, due to the presence of exudative pleurisy (Merabishvili V.M. Malignancies in the world, Russia, St. Petersburg. - SPb., IPK BIONT", 2007. - 419-422 S.; Landis S.H. et al. Cancer Statistics, 1999 // CA Cancer J Clin 1999; 49:8-31; Ling, S. et al. High-tech will improve radioterapy 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 cancerous pericardial effusion can occur when common cancers breast cancer (45-50%), stomach (30-65%), thyroid (25-45%) and some other malignant tumors. About 2% of the total number of specific pleural effusions accounts for diffuse malignant pleural mesothelioma (Kolesnikov I.S., Lytkin M.I. Surgery of the lung and pleura // HP: Medicine, 1988. - 382 S.; MalcolmM. 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; J.H. Schiller 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 increased capillary permeability in the tumor infiltration of the pleura, inflammation, irradiation, etc. Characteristic features of pleural effusion are the reduction of chest excursion and volume of breath expressed shortness of breath and pain. To prevent exudation of the traditionally used methods such as surgical (open and endoscopic) pleurectomy, chemical pleurodesis (intrapleural injection of Akrikhin, talc, tetracycline, delagila), fizi is a mini pleurodesis (electrocoagulation, argon plasma, laser, cryodestruction). Widespread intrapleural introduction of chemotherapeutic drugs such as cyclophosphamide, bleomycin, etc. However, the results of applying these methods has not been satisfactory. Physical and chemical pleurodesis can usually be achieved only partial effect is limited due to frequent obliteration of the pleural cavity, and the inaccessibility of many of its departments to conduct manipulations. High probability of resistance pleural effusions to intracavitary doing drugs (43-82% of cases) is also a frequent cause of re-accumulation abundant pleural effusion. In the foreign literature of recent years there are reports of the use of intrapleural hemoperfusion (intrathoracic chemohyperthermia - ITCH) with cisplatin and/or mitomycin. However, using this method in isolation is not allowed to reach the authors significant improvement in immediate and remote results (relapse accumulation of liquid more than 4%; the median survival of less than 5 months.) with a significant number of complications (30%) (O. Monneuse 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: 2197-2203).

In General, according to the reviewed literature, the use of the above-described isolated techniques allows to achieve complete cessation of accumulation of effusion in the pleural cavity is not more than 70-80% (Akopov A.A., Kondratyev V.B. have been Intracavitary application bleomitsetina with malignant pleurisy // Materials of the 3rd all-Russian oncological conference. SPb., - 1999. P.137-138; Moiseyenko VM Modern chemotherapy of disseminated breast cancer // Materials of the 3rd all-Russian oncological conference. SPb, - 1999. S-110; Hansen N.N., Bunn R.A. Lung cancer therapy // Taylor&Francis. 2005. - P.100-105; Sahn S.A. Pulmonary Emergencies // Churchill Livingstone, New York, 1982, c.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). It is impossible not to take into account a large number of side effects and complications in the implementation of these techniques, such as allergic reactions, respiratory distress syndrome, development of system and multiple organ failure (J.R. Campos et al. Thoracoscopic pleurodesis with talc // Chest. - 2001 Mar. - Vol.119(3). - P.801-806; Furedi A. et al. Video thoracoscopic pleurodesis in the treatment of malignant pleural effusion // Acta Chir Hung. - 1999. No. 2. - Vol.55. - P.17-19; H.H. Hansen, P.A. Bunn Lung cancer therapy // Taylor&Francis. 2005. - P.100-105; Rodriguez-Panadero F. // Monaldi Arch. Chest Dis. - 2000 Feb. - Vol.55(1). - P.17-19).

In eticholeve become obvious advantages of the introduction of combined and complex methods of elimination of hydrothorax in malignant exudative pleurisy, to eliminate these deficiencies by complement effects. The analysis of literature data showed newness "of the Method of complex treatment of malignant neoplastic lesions of the pleura, accompanied by exudative pleurisy".

Closest to the proposed method are the previously proposed method, which consists in conducting argon plasma electrocautery pleura with the subsequent performance of intraoperative photodynamic therapy photosensitizer "photoditazine and radiation of a semiconductor laser wavelength of 662 nm, with the aim of reducing tumor mass, reduction of exudation and loss of protein, reducing inflammation, intoxication and pain syndrome (patent No. 2289352, publ. 20.12.2006, Bulletin No. 35).

The advantages of the combination of argon plasma electrocoagulation treatment with photodynamic therapy added effects caused by the conduct of hyperthermic intrapleural hemoperfusion cisplatin, in order to achieve maximum cytoreductive, termination exudation and protein loss, stop inflammation, tumor intoxication and pain syndrome due to local and systemic effects.

The technical result of this method is 1) reduction of the tumor mass (cytoreductive); 2) termination of exudation and loss of protein; 3) the reduction of inflammation, intoxication and pain syndrome; 4) local and systemic cytotoxic effects of cisplatin. This is achieved through argon plasma electrocautery pleura ("ERBOTOM ICC 300; ARS-300"; ICC "ERBE VIO" - "ERBE Elektromedizin", Germany) with subsequent intraoperative conducting photodynamic therapy and hyperthermic intrapleural hemoperfusion (perfusion pump "MARS", CNIRD, Russia; physiological perfusion unit-oxygenator "MINIMAX", "Medtronic, USA).

In the clinic of the research Institute of Oncology named New University used functional complex consisting of control unit and control organotitanium, a high-frequency generator and a flexible probe electrodes. In a functional complex had software with a choice of optimum parameters of the power generator and argon consumption, allowing you to precisely control the depth and amount of exposure. Argon plasma coagulation is a method of monopolar high-frequency electrosurgery, in which the energy of the high frequency current is transmitted to the tissue in a contactless manner by means of ionized argon. Argon plasma arc is formed between the electrode and the tissue that has the lowest resistance. The resulting dehydration (desiccation) of coagulated tissue increases its resistance that Pref is the CIO to move argon arc on a piece of tissue with less resistance, ensuring the homogeneity of the zone of coagulation and controllability of the depth of the impact. The depth of coagulation depending on the power and duration of application of the electrode does not exceed 3 mm, reducing the risk of damage to major vessels and organs of the thoracic cavity. Coagulation is carried out at a power of 60 to 90 watts, at a flow rate of argon at 2.0-2.4 l/min One advantage of this method is coagulation in an oxygen-free environment that allows you to affect the fabric without substantial charring (carbonization) and smoke pleural cavity.

For photodynamic therapy was used photosensitizer "photoditazine" (registration No. 249188) based on water-soluble form of chlorin E6 with a number of biological, physico-chemical and energy characteristics that distinguish it from previously used in the clinic photosensitizers, such as: 1) strong absorption band in the red wavelength region of the spectrum (662 nm); 2) rapid pharmacodynamics (time accumulation in the tumor is 2 hours, the time for complete removal from the body - 24-36 hours); 3) high affilinet (factor accumulation in the tumor compared with normal tissue 10:1-15:1); 4) low dark toxicity, providing ease of use in clinical and outpatient settings; 5) high luminous photocytotoxic is here, associated with the active generation of singlet oxygen (75-96%) when interacting with laser radiation; 6) highly penetrating into the tissue, as the wavelength of the laser lies in the area of their optical transparency; 7) large therapeutic range of the drug; 8) low allergenicity. The radiation produced by semiconductor laser "Atcus-2" (registration No. 29/05010104/5958-04 MH RF from 26.01.04.; certificate of conformity GREW RUIM) with a power density of 300 mW/cm2; the total power of the radiation - 400-j. The dose was 1.5 mg/kg of body weight. Irradiation of the tumor was performed 2 hours after administration of the drug (the drug was administered before the operation). In addition to wearing sunglasses during the day no other protective measures are not required. The introduction of photodithazine followed by laser irradiation did not cause common phototoxic reactions. In any case it is not marked for cumulative effect.

When conducting hyperthermic intrapleural hemoperfusion (perfusion pump "MARS", CNIRD, Russia; physiological perfusion unit-oxygenator "MINIMAX", "Medtronic, USA) was used cytotoxic drug cisplatin, bifunktionalno alkylating DNA, inhibiting the biosynthesis of nucleic acids in a dose of 100 mg dissolved in 1500-3000 ml of 0.9% solution of n is sodium chloride. Hyperthermic intrapleural hemoperfusion was carried out through a standard silicone drainage tube, supplied in the kit, at a temperature of 42°C for 60 min with a feed rate of solution of 1200 ml/min

All stages of treatment were carried out sequentially during a single surgical intervention in terms of General anesthesia, adelegate ventilation in the front-side or lateral position of the patient during videothoracoscopy or open transthoracic surgery. When installed passive pleural drainage for control of hemostasis and evacuation of fluid in the nearest postoperative period (1 to 3 days).

The study included data of 6 patients at the age from 35 to 63 years, 2 women and 4 men, which from April 2007 to February 2008 in our hospital conducted a comprehensive treatment of malignant neoplastic lesions of the pleura, accompanied by exudative pleurisy. In all cases produced morphological verification process. The described method of treatment used in two patients with dissemination of the tumor in the pleura in advanced non-small cell lung cancer and four patients with diffuse malignant mesothelioma of the pleura. All patients were able to achieve immediate persistent halt the accumulation of pleural effusion p is lost. The need for repeated surgical interventions and pleural punctures did not arise. All patients intervention was performed with palliative intent. Immediately after combined treatment of patients reported subjective improvement of health, which was confirmed and objective data physical examination, improvement in clinical, biochemical and gas blood tests, x-ray data.

Inventive step of the proposed method is confirmed by the fact that in all cases (100%; N=6) completely abolished the accumulation of pleural effusion, marked improvement of function of external respiration, reduced toxicity and pain. Cases of recurrent malignant pericardial effusion in patients not selected.

As clinical samples and to confirm the terms "industrial applicability", the following clinical observations.

Example 1. Patient WMA, 44 years. Complaints at admission to intensive pain in the chest on the left, short of breath with little exertion, weakness. Clinical diagnosis: diffuse malignant mesothelioma of the pleura on the left. Exudative pleurisy. The morphological examination (biopsy of the pleura) - epithelialization malignant mesothelioma. perezia 14.05.2007, videothoracoscopy left, argon plasma pleurodesis with intraoperative photodynamic therapy (photoditazine - 1.5 mg/kg; total power of the radiation - 400 j/cm2when the power density of 300 mW/cm2and hyperthermic intrapleural hemiberlesia cisplatin 100 mg in 3000 ml of 0.9% solution of sodium chloride at a temperature of 42°C for 60 min with a feed rate of solution of 1200 ml/min Duration is 60 minutes. Dynamic clinical and radiographic observation of the absence of recurrent exudative pleurisy for 10 months (the entire period of observation).

Example 2. Patient SLS, 59 years old. Complaints upon receipt of shortness of breath on exertion, dry cough, chest pain, weakness. Clinical diagnosis: Malignant diffuse-nodular pleural mesothelioma is right with these metastases. Exudative pleurisy. The morphological examination (biopsy of the pleura) - epithelialization malignant mesothelioma. Operation 24.06.2007, Right-sided thoracotomy, argon plasma pleurodesis with intraoperative photodynamic therapy (photoditazine - 1.5 mg/kg; total power of the radiation - 400 j/cm2when the power density of 300 mW/cm2and hyperthermic intrapleural hemiberlesia cisplatin 100 mg in 1600 ml of 0.9% sodium chloride solution at t is mperature 42°C for 60 min with a feed rate of solution of 1200 ml/min The procedure takes 45 minutes. Dynamic clinical and radiological observation no recurrence of exudative pleural effusion in 9 months (the entire period of observation).

Example 3. Patient FWA, 35 years. Complaints at admission at increasing temperature up to 39°C; shortness of breath with little exertion, weakness, cough with viscous sputum, hoarseness. Clinical diagnosis: Cancer of the right upper lobe bronchus with the transition to home and metastases in the lymph nodes of the root of the lung and mediastinum. Dissemination on the pleura. Exudative pleurisy. The morphological examination (biopsy of the pleura) - usernotification adenocarcinoma. Operation 16.07.2007, argon plasma pleurodesis with intraoperative photodynamic therapy (photoditazine - 1.5 mg/kg; total power of the radiation - 400 j/cm2when the power density of 300 mW/cm2and hyperthermic intrapleural hemiberlesia cisplatin 100 mg in 2500 ml of 0.9% solution of sodium chloride at a temperature of 42°C for 60 min with a feed rate of solution of 1200 ml/min Duration is 55 minutes. Dynamic clinical and radiographic observation of the absence of recurrent exudative pleurisy 8 months (the entire period of observation).

The method of complex treatment of malignant neoplastic lesions p is Evry, accompanied by exudative pleurisy, including argon plasma electrocautery pleura when the power 60-90 W and the flow rate of argon at 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 wavelength of 662 nm, power density
300 mW/cm2and the total dose of energy of 400 j/cm2, characterized in that it additionally produce hyperthermic intrapleural hemoperfusion cisplatin 100 mg 1500-3000 ml of 0.9%sodium chloride solution at a temperature of 42°C for 60 min with a feed rate of solution of 1200 ml/min



 

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