RU2559130C1 - Method of treating advanced non-small cell lung cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology, radiation therapy and chemotherapy. The treatment of advanced non-small cell lung cancer involves the chemotherapy and two daily radiations every 5 or 6 hours for 5 days a week. For the first two weeks, the patient is exposed to the radiation twice a day in a single boost dose from 1.00 to 1.25 Gy; for the third and second weeks, the single boost dose range within 1.25 to 1.35 Gy, twice a day; for the fifth week, the single boost dose is from 1.4 to 1.45 Gy, twice a day as well. A total boost dose makes from 59 to 63 Gy. The radiation is combined with the chemotherapy by administering cysplatin 70-80 mg/m² on the 1^st and 29^th days of the radiation therapy 30-45 min before the first session and etoposide from 90 to 100 mg/m² on the 1^st-3^rd and 29^th-31^st days of the radiation therapy 1 h 20 min ÷ 1 h 40 min before the repeated exposure.

EFFECT: method provides the higher effectiveness of the radiation therapy by the most reasonable combination of the radiation and chemotherapy, as well as reduces the length of treatment and downsizes the tumour considerable that is the 50-70 times reduced tumour cell number.

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Description

The invention relates to medicine, namely to medical radiology, using radiation therapy in the treatment of non-small cell inoperable lung cancer.

In the structure of malignant oncological diseases in Russia, lung cancer, both in morbidity and mortality, especially among men, occupies a leading position. The standardized lung cancer incidence rate as of 2012 in Russia is on average 68 for men and 8.2 for women per 100,000 inhabitants. At the same time, as a rule, mainly radiation therapy is widely used. However, with its independent use it was found that it provides only a palliative effect with a total focal dose (SOD) of 40-60 Gy. In patients receiving such radiation doses, tumor growth resumes in 33-50% of cases. The greatest positive effect in patients with lung cancer is observed with SOD 70-80 Gy. However, such doses are associated with a risk of severe radiation complications from surrounding organs and tissues.

Known "METHOD FOR CONSERVATIVE TREATMENT OF PATIENTS WITH INoperable LUNG CANCER" according to patent RU 2311185, including the introduction of chemotherapy drugs, incubated with the body’s auto-medium, and radiation therapy. In this case, the bone marrow suspension of the patient taken from the ilium is incubated with chemotherapy in an thermostat at 37 ° C for 30 minutes and the patient is re-infused intravenously. After two weeks, radiation treatment is carried out in the regime of accelerated hyperfraction of 1.3 Gy, 2 fractions per day with an interval of 4 hours between fractions for 2 weeks daily. 3 such cycles are carried out, combining the administration of chemotherapy on bone marrow suspension and radiation therapy, with an interval of 2 weeks with a difference only in the radiation treatment regimen. So, during the second cycle, a single dose of radiation is 1.2 Gy twice a day with an interval of 4 hours for 2 weeks. During the third cycle - 1.1 Gy daily with an interval of 4 hours for 2 weeks. The invention improves the immediate results and quality of life of patients, reduces the side effects of antitumor therapy with nonspecific stimulation of the immune status by elements of bone marrow suspension.

The disadvantages of the method are the long course of treatment for 12 weeks with significant radiation loads exceeding the tolerance of the surrounding organs and tissues to radiation exposure.

The well-known "Method of treating locally advanced non-small cell lung cancer" according to patent RU 2489181. It includes daily local radiation therapy with a two-time focal dose (ROD) of 2 + 2 Gy to SOD 60-70 Gy. Irradiation was carried out according to a radical program on high-energy therapeutic devices, including the LUE SL - 75-5, in the regime of crushing the daily dose through two counter fields of complex configuration [E. Nemkova Abstract of the dissertation "Radiation therapy in the dynamic fractionation mode in the combined treatment of inoperable non-small cell lung cancer." - SPb., 2009]. An additional 3 times a week immediately after a session of local radiation therapy, subtotal irradiation of the upper half of the body (STOT) was performed from the jugular fossa to the diaphragm with a single dose of 0.1 Gy to achieve a total dose of 1 Gy.

The method provides a reduction in the risk of local recurrence, metastasis, complete tumor regression in 15.6% of patients, with an average life expectancy of 18 months.

The disadvantage of this method is to increase the risk of long-term negative consequences of such a radiotherapy technique.

The well-known "Method of treating non-small cell lung cancer" according to patent RU 2490037. It includes conducting sessions of local radiation therapy in the dynamic fractionation mode with a single focal dose of 2 + 2 Gy daily to a total focal dose of 60-70 Gy. In addition, an additional 3 times a week immediately after a session of local radiation therapy, subtotal irradiation of the upper half of the body (STOT) is carried out from the jugular fossa to the diaphragm with a single dose of 0.1 Gy to achieve a total dose of 1 Gy. Then, after 21-28 days after completion of local radiation therapy, at least 4 cycles of chemotherapy (CT) are performed with 3 times a week at the same time with each cycle of CTOT chemotherapy of the upper half of the body from the jugular fossa to the diaphragm with a single dose of 0.1 Gy, until the total dose of STOT at each chemotherapy cycle 0.3 Gy.

The method allows to reduce the risk of local tumor recurrence and metastasis up to 10.7% compared with previously known methods (15%), as well as the severity of complications, with achieving a complete objective response to treatment in 35.7% of patients, partial in 46, 42%

The disadvantage of this method is the significant duration of treatment and the danger of severe reactions and complications after radiation and chemotherapy.

Known methods of radiation therapy for inoperable patients with non-small cell lung cancer [Mardinsky Yu.S., Zolotkov AG Kudryavtsev D.V. The significance of radiation therapy in the treatment of lung cancer // Oncology Issues. 2006.Vol. 52 (5). S.499-504]. A total of 286 patients were treated in various ways: 1) traditional fractionation - ROD 2.0 Gy / day, in a row 5 days a week to SOD 60-64 Gy; 2) accelerated fractionation - ROD 2.5 Gy / day, every other day until SOD 66-72 Gy; 3) superfractionation of ROD 2.0 Gy / day, twice a day according to ROD 1.0 Gy / session up to SOD 60 Gy; 4) accelerated hyperfractionation by ROD 1.25 Gy, 2 times a day to SOD 67.5 - 72.5 Gy; 5) accelerated hyperfractionation with an escalation of ROD from 1.3 Gy / session to 1.6 Gy / session, 2 times a day to SOD 68 Gy. The interval between exposures during the day is 5-6 hours.

The disadvantages of the methods are the low level of realization of the direct effects associated with the long term radiation exposure to the cancerous tumor, the high total focal dose and the risk of exceeding the tolerance of the surrounding tissues.

The prototype of the invention is a method of accelerated hyperfraction with uneven crushing of the daily dose of ROD 1 + 1.5 Gy with an interval of 5-6 hours to SOD 50-60 Gy. Radiation therapy was carried out 5 days a week on the gamma-therapeutic devices "AGAT" and "ROCUS". Chemotherapy was carried out on the 1st, 8th and 15th days according to the scheme: etoposide 100 mg / m ² + cisplatin 30 mg / m ² simultaneously with the start of radiation therapy [Gulidov I.A., Zolotkov A.G., Mardinsky Yu.S. Comparison of traditional radiation therapy with the technique of accelerated hyperfraction in the chemoradiation treatment of localized small cell cancer // Siberian Oncological Journal. 2013. No1. S.12-15].

The disadvantage of the prototype lies in the fact that the proposed total focal dose of radiation is insufficient for the effective radiation of the tumor and does not take into account the kinetics of the death of tumor cells.

Our and foreign experience has allowed us to establish that the effectiveness of radiation therapy is largely determined by the regime of fractionation of the daily dose of radiation and the dynamics of the radiobiological effects associated with a change in the radiosensitivity of cancer cells during reoxygenation and an increase in their proliferative activity. Laboratory data indicate the possibility of reducing the time of radiation exposure (see figure 1) [Ivanov V.K. Mathematical modeling and optimization of radiation therapy of tumors. - M .: Energoatomizdat, 1986. 144 p .; Jeremic B., Milicic B., Milisavljevic S. Concurrent hyperfractionated radiation therapy and chemotherapy in locally advanced (Stage III) non-small-cell lung cancer: single institution experience with 600 patients. // Int. J. Radiat. Oncol. Biol. Phys. - 2012. - V.82. - P.1157-1163].

It is well known that chemotherapy (XT) has a radiosensitizing and damaging effect on the tumor. In this case, attention should be paid to the pharmacokinetic properties of the drugs used. So the kinetics of etoposide after iv administration is described by a two-phase model. In the initial phase, the half-life (T_1 / 2) is about 1.5 hours, and in the terminal phase from 4 to 11 hours. The total clearance in the terminal phase is not dose-dependent in the dose range of 100-600 mg / m ² .

The kinetics of cisplatin is more dynamic and is 15-60 minutes with rapid intravenous infusion, i.e. its appearance in blood plasma and maximum concentration are determined immediately after administration. Pharmacokinetics is also described by a biphasic curve. The elimination half-life in the initial phase is 25-49 minutes, in the final phase with normal excretory function of the kidneys - 58-73 hours (according to http: //www.breast-cance).

The technical result of the invention is to increase the level of effectiveness of radiation therapy by changing the tactics of treatment, which is to maximize the use of the synergistic effect of the most reasonable course of radiation and chemical exposure, which will shorten the treatment time and significantly reduce the volume of the tumor.

The essence of the invention, including chemotherapy and daily two-time exposure to radiation with an interval of 5-6 hours for 5 days a week. In the first two weeks, irradiation is carried out 2 times a day for ROD from 1 to 1.25 Gy. In the third and fourth week, they are also irradiated 2 times a day with ROD from 1.25 to 1.35 Gy, and in the fifth week, daily with ROD from 1.4 to 1.5 Gy. The entire irradiation rate is SOD from 59 to 63 Gy. To ensure a synergistic effect in the process of radiation therapy, cisplatin is administered from 70 to 80 mg / m ² on days 1 and 29 for 30-45 minutes and etoposide is administered 1 hour 20 minutes to 1 hour 40 minutes before re-exposure from 90 to 100 mg / m ² on the 1st ÷ 3rd, as well as on the 29th ÷ 31st days.

List of figures

Figure 1. Schemes for laboratory studies of radiation therapy: 1 - uniform crushing of the daily dose, 2 - dynamic hyperfractionation (DHF).

The procedure for implementing the method

The laboratory studies conducted by the authors indicate that it is possible to increase the effectiveness of DHF on cancer cells, which can significantly reduce their number by 50-70 times compared to conventional daily dose hyperfraction. In this case, the treatment compared with the prototype can be reduced to 5 weeks (Fig. 1, 2).

Previously, the authors also found that the effectiveness of radiation therapy is largely determined by the fractionation regime of the daily dose of radiation. At the same time, non-small cell lung cancer (NSCLC) cells have a low ability to repair sublethal injuries, which makes them more sensitive to radiation therapy (RT) in the hyprefraction mode when radiation doses of less than traditional 2 Gy per fraction are used [Zolotkov AG, Mardinsky Yu.S., Gulidov I.A. Therapeutic radiology. A guide for doctors "Radiation therapy of lung tumors / Ed. A.F. Tsyba, Yu.S. Mardynsky. - M., 2010. S. 110-173]. To enhance the effect on the tumor process, radiation therapy is combined with the effects of chemotherapeutic drugs - cisplatin and etoposide. Drugs are administered intravenously.

In accordance with the essence of the invention, the course of radiation therapy is a daily two-time radiation exposure with an interval of 5-6 hours for 5 days a week. In the first two weeks, daily irradiation with two fractions per day according to a genera of 1.00 to 1.25 Gy is carried out. This effect is justified by the difference in the rate of restoration of sublethal damage to tumor and normal cells, as well as the leveling of the oxygen effect, which makes it possible to enhance the damaging effect of radiation on the tumor while reducing damage to healthy tissues. In addition, the proposed fragmentation of the daily radiation dose makes it possible to increase the total focal dose to the target by 15-20% without increasing the number and severity of radiation reactions.

In the third and fourth week, they are also irradiated 2 times a day according to a genera of 1.25 to 1.35 Gy. In the fifth week, irradiation is carried out daily by ROD from 1.4 to 1.5 Gy. The entire irradiation rate is SOD from 59 to 63 Gy (see Table 1).

To enhance the effect of radiation therapy on the tumor process, chemotherapy is performed using drugs: for 30–45 min, cisplatin is from 70 to 80 mg / m ² before irradiation on days 1 and 29 of radiation therapy. Before the second irradiation session, etoposide from 90 to 100 mg / m ² is administered on days 1-3 and also on days 29-31 of treatment for 1 hour 20 minutes ÷ 1 hour 40 minutes.

Topometric preparation for radiation treatment is carried out in accordance with existing standards in the supine position with his arms raised behind his head. Irradiation is carried out on devices for remote megavolt therapy.

Clinical examples of the implementation of the method

Example No. 1

Patient R-V (63 years old), medical history number - 4031. He was treated in the department of radiation and surgical treatment of diseases of the thoracic region with a diagnosis of Central cancer of the upper lobe of the right lung T2N2M0 (III A stage), squamous version. A radical course of radiation therapy was carried out in the period from 07/11/12 to 08/22/12 in the regime of dynamic fractionation of the daily dose - in the first two weeks, a daily two-time radiation exposure was performed according to a genera of 1.00 Gy with an interval of 5-6 hours for 5 days a week. In the third and fourth weeks, they are also irradiated 2 times a day according to a genera of 1.25 Gy. At the 5th week, irradiation was carried out daily for 5 days, twice a day, ROD 1.4 Gy. The patient received a total focal dose of 59 Gy.

Chemotherapy was performed according to the cisplatin regimen of 70 mg / m ² on days 1 and 29 + etoposide 90 mg / m ² on days 1-3, 29-31. In this case, cisplatin was administered 30-45 min before the first irradiation session, and etoposide was administered 1 hour 30 min before the second irradiation of 90 mg / m ² on days 1-3 and 29-31 of treatment.

At the end of treatment, a marked> 50% tumor regression was noted. The initial tumor size was 45 × 45 × 40 mm, the tumor size after treatment was 16 × 21 × 18 mm. The treatment was satisfactory.

Example 2

Patient B. (58 years old), the medical history number is 3757. He was treated in the department of radiation and surgical treatment of diseases of the thoracic region with a diagnosis of Central cancer of the upper lobe of the right lung T2N2M0 (III A stage), squamous version. A radical course of radiation therapy was carried out from 06/21/12 to 07/25/12 in the regime of dynamic fractionation of the daily dose - in the first two weeks, a daily two-time radiation exposure was performed according to a genera of 1.10 Gy with an interval of 5-6 hours for 5 days a week. In the third and fourth weeks, they are also irradiated 2 times a day according to a genera of 1.30 Gy. At the 5th week, irradiation was carried out daily for 5 days twice as a ROD of 1.45 Gy. The patient received a total focal dose of 62.5 Gy.

Chemotherapy was performed according to the cisplatin regimen of 80 mg / m ² on days 1 and 29 + etoposide 100 mg / m ² on days 1-3, 29-31 of treatment. In this case, cisplatin was administered 30-45 min before the first irradiation session, and etoposide was administered 1 hour 30 min before the second irradiation.

At the end of treatment, a complete regression of the tumor was noted (initial tumor size 40 × 35 mm). The treatment was satisfactory.

Example 3

Patient An, date of birth 03.08.1937 (57 years old), medical history number 1387. He was treated in the department of radiation and surgical treatment of diseases of the thoracic region with a diagnosis of Central cancer of the right lung T2N1M0 (II stage B), squamous version. A radical course of radiation therapy was carried out in the period from 05/10/94 to 06/22/94 in the regime of dynamic fractionation of the daily dose - in the first two weeks a daily two-time radiation exposure was performed according to a genera of 1.25 Gy with an interval of 5-6 hours for 5 days a week. In the third and fourth weeks, they are also irradiated 2 times a day according to a genera of 1.35 Gy. At the 5th week, irradiation was carried out daily for 5 days once with a delivery of 1.50 Gy. The patient received a total focal dose of 67 Gy.

Chemotherapy was performed according to the cisplatin regimen of 80 mg / m ² on days 1 and 29 + etoposide 100 mg / m ² on days 1-3, 29-31 of treatment. In this case, cisplatin was administered 30-45 min before the first irradiation session, and etoposide was administered 1 hour 30 min before the second irradiation.

At the end of treatment, marked regression of the tumor was noted. The treatment was satisfactory.

An example implementation of the treatment method of the prototype.

Example 4

Patient M., birth date 02/30/1940 (55 years), medical history number - 2279. He was treated in the department of radiation and surgical treatment of diseases of the thoracic region with a diagnosis of Central cancer of the right lung T2N2M0 (III A stage), squamous version. A radical course of radiation therapy was carried out in the period from 07/04/95 to 08/14/95, in the uniform hyperfraction mode to a total focal dose of 60 Gy. At the end of treatment, a slight regression of the tumor was noted. The treatment was satisfactory.

Confirmation of the achievement of the technical result

The main idea of the proposed method of dynamic hyperfractionation (DHF) is to gradually increase the daily training dose by the end of the course of radiation therapy. Such a course of radiation therapy allows you to quickly bring the necessary focal dose with maximum tumor damage and preservation of intact tissues (see table 1 and table 2). For comparison, Table 2 shows the results of the treatment of lung cancer in the uniform hyperfractionated (RHF) mode and the dynamic fractionation mode (DHF). The course of treatment in the RGF regimen lasts 6 weeks to a SOD of 60 Gy, while the course of treatment in the RGF regimen lasts 5 weeks with obtaining the best result with a SOD from 59 to 63 Gy.

In the vast majority of patients, non-small cell lung cancer of the IIA-IIB stage took place.

The average age of patients in the group was, respectively: with DHF - 56.9 years, with treatment according to the prototype 61 years.

Patients satisfactorily underwent DHF radiation therapy. Radiation reactions in the form of esophagitis and pulmonitis of varying severity, fibrosis did not significantly differ in both groups of patients with RHF and DHF. The same applies to hematological reactions.

When assessing the direct reactions of the tumor after the completion of radiation therapy, pronounced regression (reduction of the tumor by more than 50%) was observed in 11 (79%) patients with DHF and only 3 (6%) patients with RHF. In DHF, in one observation, complete regression of the tumor was noted, which was not observed in the control group. It should be emphasized that the direct response of the tumor to radiation therapy is the most important prognostic factor affecting the immediate and long-term results of the treatment of malignant neoplasms. This factor convincingly testifies in favor of a significant advantage of the proposed method of radiation therapy - dynamic hyperfractionation of the radiation dose.

A comparative assessment of the results of radiation therapy for patients with lung cancer according to the method of the proposed method of treatment (DHF) compared with the traditional method (RHF) was carried out on a group of 28 patients with II-IV stages of the disease (Table 2).

Claims (1)

A method of treating inoperable non-small cell lung cancer, including chemotherapy and daily two-time radiation exposure with an interval of 5-6 hours for 5 days a week, characterized in that in the first two weeks, irradiation is carried out 2 times a day for ROD from 1.00 to 1.25 Gy; in the third and fourth week, they are also irradiated 2 times a day for ROD from 1.25 to 1.35 Gy, and in the fifth week, daily twice a day for ROD from 1.4 to 1.45 Gy, however, the entire course of exposure is SOD from 59 to 63 Gy, with simultaneous chemotherapy, for which on the 1st and 29th days of radiation uu for 30-45 minutes before the first treatment is administered 70-80 mg / m ² cisplatin and 1-3 and 29-31 days of radiotherapy for 1 h 20 min ÷ 1 h 40 min before re-exposure is administered from 90 to 100 mg / m ² etoposide.

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