RU2590866C1 - Method of combination treatment of operable non-small cell lung cancer stage iii - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention can be used to increase efficiency of combination treatment of operable non-small cell lung cancer (NSCLC) of stage III. One performs teletherapy (RTT) in hyperfractionation mode at 1.3 Gy × 2 times a day for 5 days a week, 3 weeks to total basic dose of 40 Gy. At that, RTT is carried out in parallel with two courses of chemotherapy according to the schedule paclitaxel 175 mg/m² and carboplatin AUC 6 in 1st and 23rd days with underlying local hyperthermia (LH) 2 times a week, total of 10 sessions. Besides, LH is carried out 2 hours before radiation or directly after introduction of chemopreparations for 60 minutes at a temperature of 41-44 °C. In 3 weeks after chemoradiation therapy radical surgery is performed.

EFFECT: method provides improved survival rate in patients with stage III NSCLC ensured by optimising objective response to therapy and extent of tumour process, reducing rate of local recurrences, remote metastases and complications of combined treatment.

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Description

The invention relates to the field of medicine, oncology, and can be used for the combined treatment of operable non-small cell lung cancer (NSCLC) stage III.

To date, the main and only radical method of treating patients with resectable forms of NSCLC is surgical, which is most effective in the early stages of the disease, when it is used alone, and in locally advanced forms, in combination with radiation and / or drug antitumor therapy [1, 2, 3].

Using traditional methods of radiation treatment, it is impossible to eradicate the disease in most patients with locally advanced NSCLC [4, 5]. It seems promising to study non-standard modes of fractionation of the radiation dose (hypo-, hyperfractionation, dynamic fractionation), as well as control of tissue radiosensitivity by using various kinds of radio modifiers (hyperthermia, hypoxiradiotherapy, electron-acceptor compounds, chemotherapy) [6, 7].

When conducting preoperative radiation therapy, the additional use of cytostatics as induction chemotherapy allows to achieve higher objective response rates (55.2-76.9%), including complete pathomorphological regression of the tumor process (27-34.6%) [8, 9], without increasing the level of postoperative mortality (3, 4%). It should be noted that to increase the effectiveness of the combined treatment of NSCLC, approaches to chemotherapy in combination with local hyperthermia are also being developed [10, 11].

Closest to the proposed is a method of treating locally advanced NSCLC with invasion into the chest wall [12], which includes remote radiation therapy in a total focal dose (SOD) of 13.6-70 Gy and radiofrequency capacitive hyperthermia 1 or 2 sessions per week after exposure to within 30-60 minutes (only 1-12 sessions), which in some cases allows surgical treatment. However, when conducting radiation therapy in the traditional fractionation mode in combination with local hyperthermia, despite the high objective response figures, the resectability of the tumor process remains unsatisfactory and does not exceed 33.3%, which, in turn, results in low survival of patients with locally advanced NSCLC. In addition, as a result of the treatment, such side effects as pain syndrome (60%) and shortness of breath (15%) are quite common, cases of pneumothorax and skin abscesses are described. All this indicates the lack of effectiveness of the applied method of treatment.

A new technical result is an improvement in patient survival by increasing the objective response and resectability of the tumor process, reducing the frequency of local relapses, distant metastases, and complications of the combined treatment.

To achieve a new technical result in the method of combined treatment of stage III non-small cell lung cancer, including remote radiation therapy and local hyperthermia, radiation therapy is carried out in a hyperfraction mode of 1.3 Gy × 2 times a day, 5 days a week, 3 weeks to the total focal doses of 40 Gy in parallel with two courses of chemotherapy according to the paclitaxel 175 mg / m ² regimen and carboplatin AUC 6 on the 1st and 23rd day against the background of local hyperthermia 2 times a week, only 10 sessions, 2 hours before irradiation or immediately after in eniya chemotherapeutic agents for 60 minutes at a temperature of from 41 to 44 ° C, then, after 3 weeks after chemoradiotherapy perform radical surgical treatment.

The proposed method meets the criterion of "novelty," because, unlike the prototype, it has the following significant distinguishing features:

a) treatment is performed by an operable patient with NSCLC;

b) irradiation is carried out at the preoperative stage in the regime of hyperfraction of 1.3 Gy × 2 times a day, 5 days a week, 3 weeks up to SOD 40 Gy in parallel with two chemotherapy courses according to the paclitaxel 175 mg / m ² and carboplatin AUC 6 in 1 regimen the 23rd and 23rd day;

c) local hyperthermia is carried out 2 hours before irradiation or immediately after the administration of chemotherapy for 60 minutes at a temperature of 41 to 44 ° C, the frequency of hyperthermia sessions is 2 times a week, only 10 sessions;

d) for the purpose of polyradiomodification, two chemotherapeutic agents are used (paclitaxel, carboplatin) and local hyperthermia;

e) after the end of preoperative chemoradiotherapy against the background of local hyperthermia, after 3 weeks in all cases a radical surgical intervention is performed.

When studying the prior art of the proposed combination of essential features were not identified, thus we can conclude that the proposed method meets the criterion of "inventive step".

The invention meets the criterion of "industrial applicability", as it has been tested in clinical practice for the combined treatment of patients with operable stage III NSCLC.

The process is carried out as follows: 1 st and 23 th days carried out by two cycles of chemotherapy paclitaxel 175 mg / m ² / in infusion over 3 hours and carboplatin AUC 6 / drip; carry out local hyperthermia on a Celsius TCS apparatus (Germany) from 1 to 32 days of preoperative chemoradiotherapy 2 times a week (10 sessions) immediately after administration of chemotherapy or 2 hours before irradiation for 60 minutes at a temperature of 41 to 44 ° C; from 1 to 19 days, remote radiation therapy is carried out on a Theratron Equinox 1.25 MeV device (Canada) in a hyperfraction mode of 1.3 Gy × 2 times a day, 5 days a week, 3 weeks to a total focal dose of 40 Gy; 3 weeks after the end of chemoradiotherapy, radical surgical treatment is performed.

The rationale for the method: radiation therapy at the preoperative stage allows you to translate a locally spread tumor into a resectable state, as well as reduce the risk of implantation, lymphogenous and hematogenous metastasis during surgical trauma that accompanies a lung resection. Moreover, it is known that remote radiation therapy in the usual fractionation mode (2 Gy × 1 time per day, 5 days a week, 6 weeks up to SOD 60 Gy) does not provide acceptable survival rates for patients with stage III NSCLC. In this regard, at present, when conducting radiation therapy, non-standard fractionation of the dose of radiation is actively used, which allows to expand the radiotherapy interval, that is, to selectively enhance tumor damage and reduce radiation load on normal tissues [13].

One of the rational approaches to improving the results of combined treatment of NSCLC can be considered the use of systemic chemotherapy, which at the preoperative stage has a direct cytoreductive effect against the primary tumor, mediastinal lymphogenous metastases and distant hematogenous micrometastases [14].

However, despite the large number of works devoted to the study of preoperative chemoradiotherapy, there is still no consensus on the fractionation regimen and radiation dose, which varies significantly from 42 to 60 Gy, and chemotherapy, which consists mainly of doublets based on platinum preparations, demonstrates various efficacy and tolerability [8, 9].

For many years, biological response modifiers, in particular local hyperthermia, have been used to enhance the damaging effects of chemoradiotherapy on tumor tissue. According to a number of studies [15, 16], hyperthermia has positively proven itself when used in combination with chemoradiotherapy in patients with inoperable NSCLC, which results in a statistically significant increase in objective response and overall survival. However, in the world literature there is no data on the use of preoperative chemoradiotherapy with local hyperthermia as part of the combined treatment of operable stage III NSCLC.

Due to the fact that chemotherapy reduces the tolerance of normal tissues to radiation exposure, in our proposed method, radiation therapy was performed using the hyperfraction regimen with daily fragmentation of the radiation dose (1.3 Gy × 2 times a day, 5 days a week to SOD 40 Gy ), which allows, on the one hand, to reduce the duration of radiation treatment to 3 weeks, to increase the frequency of objective response and resectability of the tumor process, and, on the other hand, to reduce the number of radiation reactions and complications, which is especially important for patients, torym planned radical surgery.

In order to prevent the development of local relapses, distant metastases, and improve the survival of operable patients with stage III NSCLC, preoperative radiation therapy is carried out simultaneously with two chemotherapy courses according to the paclitaxel / carboplatin regimen on the 1st and 23rd day, using full therapeutic dosages of cytostatics, which first they have an independent antitumor therapeutic effect, and subsequently, as the concentration and concentration of drugs in the tumor are eliminated and reduced, radiosens are additionally realized liberating effects.

Local hyperthermia is carried out on a Celsius TCS apparatus (frequency 13.56 MHz) immediately after the administration of chemotherapy or 2 hours before irradiation, which is aimed at improving the tolerability of the combined treatment. For optimal impact on the tumor site and the protection of normal tissues, the following regimen of local hyperthermia is used - 2 times a week (interval 2-3 days), only 10 sessions, the temperature range is 41-44 ° C and the duration of the hyperthermia session is 60 minutes, which ensures both own cytotoxic and modifying effect. It should be noted that when conducting preoperative chemoradiotherapy against the background of local hyperthermia, the phenomenon of polyradiomodification, based on the use of sensitizing factors of various mechanisms of action, is used to enhance tumor damage.

The time interval between the end of preoperative chemoradiotherapy with local hyperthermia before radical surgical treatment was increased from 2 to 3 weeks, as a result of which reparative processes did not suffer and intra-and postoperative complications in patients with stage III NSCLC were avoided.

Thus, the combined treatment of operable stage III NSCLC, including preoperative chemoradiotherapy with local hyperthermia and radical surgery, improves patient survival by increasing the objective response and resectability of the tumor process, reducing the frequency of local relapses, distant metastases and complications of the treatment.

Clinical example

Patient Z., 62 years old. Diagnosis: peripheral cancer of the upper lobe of the right lung. Art. III, T ₂ N ₂ M ₀ . Histology is a low-grade adenocarcinoma. Combined treatment was performed by the claimed method: 09/12/2014 and 01/10/2014 - 2 courses of chemotherapy paclitaxel at a dose of 280 mg iv drip for 3 hours and carboplatin at a dose of 460 mg iv drip; from September 12, 2014 to October 10, 2014 - 10 sessions of local hyperthermia (2 times a week, an interval of 2-3 days, immediately after the administration of chemotherapy or 2 hours before irradiation at a temperature of 41 to 44 ° C for 60 minutes); from 09/12/2014 to 09/26/2014 - remote radiation therapy in the hyperfraction mode of 1.3 Gy × 2 times a day, 5 days a week, 3 weeks up to SOD 40 Gy. The patient underwent satisfactory preoperative chemoradiotherapy with local hyperthermia, and no side effects were detected. During the control examination according to the results of spiral computed tomography - a partial regression of the tumor (the process in the lung decreased from 5 cm to 2 cm). 10/23/2014 the patient underwent a radical operation - upper lobectomy on the right. A histological examination of postoperative material revealed a 3 degree of therapeutic tumor pathomorphism. The immediate postoperative period was uneventful, the sutures were removed on the 12th day after the operation. No complications were observed. The patient was discharged on the 16th day after the operation from the clinic in satisfactory condition. During dynamic observation, data for relapse and metastases were not obtained, there were no postradiation complications.

This method treated 3 patients with operable NSCLC IIΙΑ-IIIB stage at the age of 54-64 years. In 2 cases, patients are men, in 1 case - a woman. The histological type was dominated by squamous cell carcinoma - 2 cases, adenocarcinoma - 1 case. Despite the multicomponent preoperative treatment, all patients underwent it in full without side effects. When assessing the objective effect, complete regression was detected in 1 patient, partial regression was recorded in 2 patients. Surgical treatment was performed in all patients in a radical volume - 3 lobectomies were performed. No intra- and postoperative complications were detected, reparative processes proceeded without features. The period of observation of patients was 4-20 months, at the stages of examination of patients after the combined treatment of relapses, metastases and post-radiation complications were not recorded.

Thus, the use of this treatment method allows to achieve a new technical result, namely, to improve the survival of patients with operable NSCLC by increasing the objective response and resectability of the tumor process, reducing the frequency of local relapses, distant metastases and complications of the combined treatment.

Information sources

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Claims (1)

A method for the combined treatment of operable non-small cell lung cancer of stage III, including remote radiation therapy and local hyperthermia, characterized in that radiation therapy is carried out in a hyperfraction mode of 1.3 Gy × 2 times a day, 5 days a week, 3 weeks to a total focal dose 40 Gy in parallel with two courses of chemotherapy according to the paclitaxel 175 mg / m ² regimen and carboplatin AUC 6 on the 1st and 23rd day against the background of local hyperthermia 2 times a week, only 10 sessions, 2 hours before irradiation or immediately after administration chemopr Paratov for 60 minutes at a temperature of from 41 to 44 ° C, 3 weeks after chemoradiotherapy perform radical surgical treatment.