RU2599043C1 - Method of combination treatment of locally advanced rectal cancer - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, oncology, methods of combination treatment of locally advanced rectal cancer (RC). Performed is pre-operative gamma-ray teletherapy (GRT) with underlying administration of chemopreparations and local hyperthermia. Herewith GRT is performed in the multi-fractionation mode by 1.3 Gy × 2 times a day, 5 days a week for 4 weeks with underlying oral administration of capecitabine in the dose of 825 mg/m² × 2 times a day every 12 hours on the days of GRT. Local hyperthermia is performed with underlying chemoradiation therapy 3 times a week 3 hours prior to the radiation session at the temperature of 42-44 °C during 45-60 minutes, total 10 sessions.

EFFECT: method provides improved survival rate of RC patients at reduction of frequency of local recurrence, distant metastasis, higher quality of life.

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Description

The invention relates to medicine, specifically to oncology, and in particular to methods for the combined treatment of locally advanced colorectal cancer (PKC).

Despite the certain successes of the surgical treatment method, its use in an independent version in patients with II-III stage of PKK leads to unsatisfactory results. The frequency of local relapses can reach 30-43%, which, in turn, negatively affects the level of overall 5-year survival [3], which with locally advanced forms of the disease does not exceed 20-30% [5]. In addition, at present, the main goal of treating patients with PKK is not only full recovery, but also the preservation of the main function of the rectum - controlled defecation. Such an approach requires the use of high-tech multicomponent treatment programs that organically combine surgical technologies with the latest achievements of radiation and drug therapy.

Among the options for combined treatment of resectable colorectal cancer, one of the most justified is the use of preoperative radiation therapy (RT) in combination with the use of various radio modifiers.

Most large multi-year randomized trials of the last 30 years show a high efficacy of combination RT and radical surgery [8, 12]. Conducting RT in the preoperative period leads to a significant decrease in the number of local relapses when compared with radical surgical treatment in an independent version [6]. Significant regression of the primary tumor during irradiation creates subsequent conditions for more frequent sphincter-preserving operations [4, 10], which improves the quality of life of patients with PKK.

There is a wide variety of preoperative radiotherapy techniques, recommended exposure volumes, as well as the intervals between its completion and surgical intervention. The use of "short" courses of preoperative RT in large fractions up to a total focal dose of 25 Gy also reduces the frequency of local relapses. However, a significant drawback of such medical technologies is the need to perform surgical intervention immediately after completion of irradiation, which does not allow the manifestation of therapeutic pathomorphism. However, one of the tasks of neoadjuvant treatment is to reduce the size of the primary tumor, which expands the indications for sphincter-preserving operations [2].

The radiosensitivity of tumor cells depends on a large number of factors, two of which are clearly dominant: the number of tumor cells in a state of hypoxia, and the number of non-proliferating resting clonogenic elements. Guaranteed lethal damage to hypoxic cells requires a very high dose of radiation (approximately three times the dose required for the death of oxygenated cells), which exceeds the tolerance of adjacent normal tissues.

The desire to increase a single and / or total focal dose of radiation can lead to an increase in the number of local radiation reactions, which negatively affects the results of the surgical stage of combined treatment [1, 7]. To enhance the effect of radiation and improve the immediate results of neoadjuvant radiation therapy, various radio modifiers are used. The main purpose of their use is to minimize the radioresistance of hypoxic tumor cells, thereby increasing the effectiveness of radiation therapy, namely, to obtain as a result of neoadjuvant treatment the maximum regression of the tumor, which contributes to a greater number of sphincter-preserving operations, and in some cases allows for complete regression of the primary tumor [ 9]. However, there are no generally accepted recommendations for choosing the type of modifier. Most often they use local microwave hyperthermia, electron-acceptor compounds, hyperglycemia, a number of cytostatics (5-fluorouracil, capecitabine, etc.), as well as their combinations. From this point of view, the tumor-activated drug capecitabine, which has low and well-controlled toxicity, as well as the possibility of use on an outpatient basis, is extremely attractive.

To increase the effectiveness of radiation / chemoradiotherapy in patients with colorectal cancer, the use of local hyperthermia (LHT), which significantly increases the effectiveness of both radiation and chemotherapy, is promising.

The fact that there is no generally accepted tactic for the combined treatment of PKK is obvious. In modern conditions, an increase in the effectiveness of treatment for RPK is seen not only in reducing the frequency of local relapses and improving long-term results at a temperature of 42-44 ° C for 45-60 minutes, only 10 treatment sessions, but also in an effort to ensure an optimal level of quality of life for radically treated patients.

Closest to the claimed method (prototype) is a method that includes at the preoperative stage: remote radiation therapy of ROD 5 Gy for 5 days in combination with local microwave hyperthermia at a temperature of 42.5-43 ° C for 60 minutes at 3, 4 and 5 days after radiation therapy sessions. Intrarectally with an exposure of 6 hours, a composite mixture is introduced containing sodium alginate, a 2% solution of dimethyl sulfoxide and 5-fluorouracil on the 1st, 2nd and 4th days before radiotherapy sessions. On days 3 and 5 with the same exposure, the indicated composite mixture is introduced containing metronidazole instead of 5-fluorouracil. Next, surgery is performed [RF Patent No. 2234318].

The disadvantages of this method are: the insufficient duration of the course of remote radiation therapy does not create conditions for the effect of reducing the size of the tumor, thereby not creating additional conditions for increasing the frequency of sphincter-saving operations. Also, the irradiation regime in large fractions of 5 Gy creates a significant radiation burden on healthy organs and tissues, which contributes to the risk of developing local radiation reactions; the lack of technical ability to cool the skin surface in the area of LHT does not allow to supply large power to the tumor, since the risk of developing thermal burns of the skin is significantly increased.

A new technical result is an improvement in the survival rates of patients with colorectal cancer by increasing the effectiveness of neoadjuvant treatment by reducing the incidence of local relapses, distant metastases and improving the quality of life.

To solve the problem in the Method for the combined treatment of locally advanced colorectal cancer, including preoperative remote radiation therapy with the introduction of chemotherapy and local hyperthermia, characterized in that the remote gamma therapy is carried out in multifraction mode at 1.3 Gy × 2 times a day, 5 days a week for 4 weeks amid oral capecitabine in a dose of 825 mg / m ² × 2 times a day at intervals of 12 hours per days of radiotherapy, local hyperthermia is carried out at f not chemoradiotherapy 3 times per week for 3 hours prior to irradiation session at a temperature of 42-44 ° C for 45-60 min for a total of 10 sessions.

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

a) radiation therapy is carried out in multifraction mode to a total dose of 54 Gy;

b) capecitabine is used from chemotherapy in a dose that provides a radiosensitizing effect and does not cause toxic effects;

c) carry out local hyperthermia 3 times a week 3 hours before the irradiation session at a temperature of 42-44 ° C for 45-60 minutes, a total of 10 sessions.

Due to the presence of these features in this method, as well as their use in combination and a certain sequence of actions, we can conclude that the proposed method is “inventive step”.

The invention meets the criterion of "industrially applicable", because it has been used in clinical practice for the treatment of patients with colorectal cancer.

The method is as follows: radiation therapy is carried out on a Theratron Equinox 1.25 MeV apparatus (Canada) in a multifraction mode of 1.3 Gy × 2 times a day, 5 days a week until a total dose of 54 Gy, chemotherapy is carried out simultaneously with the start of radiation therapy capecitabine at a dose of 825 mg / m ² × 2 times a day with an interval of 12 hours on the days of radiation therapy, and all chemo-radiation treatment is carried out against the background of local hyperthermia, which is carried out on a Celsius TCS apparatus (Germany) according to the scheme: 3 times a week for 3 hours before a radiation session at a temperature of 42-44 ° C for 45-60 min for a total of 10 sessions.

Justification of the method: application - only with the remote method of irradiating tumors of the ampulla of the rectum, the clinical volume of irradiation includes pararectal fiber containing regional lymph nodes of the first and second stages of metastasis, which may contain microscopic agents of tumor cells (micrometastases), even in the initial stages of the disease. In this case, the total radiation dose should not be less than 40 Gy.

Rectal adenocarcinoma refers to tumors that are characterized by a rapid growth rate and moderate radiosensitivity. Such tumors require summarizing unitary doses. However, under such conditions, there is a danger of damage to normal tissues. To avoid this, it is advisable to use daily fragmentation of the unit doses into separate fractions.

The multifraction mode with daily dose fragmentation, which implies an increase in the number of fractions compared with the classical fractionation mode, allows the maximum daily dose to be adjusted to the tumor, taking into account the recovery time of sublethal and potentially lethal damage to normal tissues (5 hours on average), which is the prevention of the development of acute radiation reactions .

As a radiosensitizer, the cytostatic capecitabine at a dose of 825 mg / m2 2 times a day on the days of radiation therapy is administered throughout the course of radiation therapy. This drug is a prodrug. Capecitabine is a fluoropyrimidine carbamate that converts to 5-fluorouracil primarily in tumor cells using the higher activity of the thymidine phosphorylase (TF) enzyme in tumor tissue compared to normal tissue. Preclinical studies have shown that radiation therapy can regulate the expression of TF by tumor cells upward, resulting in a selective synergistic effect between gamma therapy and capecitabine. It is also known that xeloda inhibits the formation of sublethal damage to tumor cells that occur during fractionated radiation therapy, and inhibits the cell cycle in the S phase, thereby exerting a pronounced radiosensitizing effect. In clinical trials of capecitabine (xeloda) phase I and II for colorectal cancer for long-term use during radiation therapy, the recommended dose of 825 mg / m ² administered twice a day was determined [15].

During radiation therapy, hyperthermia leads to increased blood flow, thereby improving tumor oxygenation. In addition, partial or complete blockage of the restoration of sublethal and potentially lethal post-radiation injuries occurs. As a result of the simultaneous use of hyperthermia and chemotherapy, there is an increase in perfusion in the tumor tissue, which contributes to the absorption of chemotherapy through the cell membrane. In addition, high temperature accelerates chemical reactions and improves the effectiveness of chemotherapy [11].

The method is illustrated by the following examples.

просвета прямой кишки за счет экзофитного компонента; По данным магнитнорезонансной томографии органов малого таза от 7 мая 2015 года на расстоянии 70 мм от анального сфинктера отмечается поражение стенок прямой кишки протяженностью 40 мм в виде неравномерного утолщения от 12 до 22 мм. Просвет кишки неравномерно сужен до 4-5 мм на проксимальном уровне опухоли. Наружный контур прямой кишки нечеткий.Example No. 1: A patient Sh. 52 years old has been observed at the Tomsk Research Institute of Oncology since May 2014 with a diagnosis of cancer of the lower ampulla of the rectum, verified as moderate adenocarcinoma. Data from a comprehensive examination before treatment: With fibrocolonoscopy from May 13, 2015, there is a bright red tuberous colorectal tumor located on the right semicircle 7 cm from the Z-line with a length of 4 cm, occupying $${}^{\mathrm{one}}{/}_2$$

rectal lumen due to exophytic component; According to magnetic resonance imaging of the pelvic organs of May 7, 2015 at a distance of 70 mm from the anal sphincter, damage to the walls of the rectum with a length of 40 mm is observed in the form of an uneven thickening from 12 to 22 mm. The lumen of the intestine is unevenly narrowed to 4-5 mm at the proximal level of the tumor. The external contour of the rectum is fuzzy.

In terms of combined treatment, from May 26, 2014 to June 26, 2014, a distance gamma therapy course was carried out in multifraction mode at 1.3 Gy × 2 times a day, 5 days a week against the background of oral administration of capecitabine at a dose of 825 mg / m2 × 2 times a day with an interval of 12 hours on the days of radiation therapy. Local hyperthermia was carried out against the background of chemoradiotherapy 3 times a week 3 hours before the irradiation session at a temperature of 42-44 ° C for 45-60 minutes, a total of 10 sessions. No acute radiation reactions were observed.

The effectiveness of the treatment was evaluated 6 weeks after the end of the course of radiation therapy. The prevalence of the primary rectal tumor in this patient changed as follows: with fibrocolonoscopy on August 8, 2014, 8 cm from the Z-line, the mucosal infiltration site with ulcerations on the surface, 2 cm long. Conclusion: Colorectal tumor, condition after chemoradiotherapy, partial regression; Magnetic resonance imaging of the pelvic organs from August 7, 2015 at a distance of 75 mm from the anal sphincter determines the zone of local thickening of the right wall of the rectum with a length of up to 25 mm, there is no data for the presence of an exophytic component, the external contour of the intestine is clearly defined at the level of the above pathological formations.

At the final stage of the combined treatment on August 15, 2014, an operation was performed in the amount of low anterior resection of the rectum. The perioperative period was uneventful. Histology (operational material): moderately differentiated adenocarcinoma with invasion to the muscle layer of the colon without metastases to regional lymph nodes. Therapeutic pathomorphism of 2 degrees.

During the follow-up examination of April 2015, no data were found for relapse / progression of the disease.

просвета кишки, оставляя свободной только часть левой стенки; При магнитнорезонансной томографии органов малого таза от 18 августа 2014 года на 95 мм от внутреннего сфинктера определяется блюдцеобразная опухоль, протяженностью до 40 мм, занимающая 3/4 окружности прямой кишки. Наружный контур на уровне образования на фоне артефактов оценить сложно, однако имеются веские подозрения на краевую инфильтрацию клетчатки справа, просвет кишки неравномерно сужен, проходимость сохранена. В параректальной клетчатке на уровне верхне- и среднеампулярного отделов, а также по ходу ветвей верхней прямокишечной артерии определяются множественные лимфоузлы до 3-10 мм. Собственная фасция на уровне образования четко не определяется.Example No. 2: Patient S., 55 years old, has been observed at the Tomsk Research Institute of Oncology since August 2014 with a diagnosis of cancer of the middle ampulla of the rectum, verified as adenocarcinoma of moderate differentiation. Data from a comprehensive examination before treatment: with fibrocolonoscopy from August 20, 2014: by 10 cm from the Z-line is determined saucer-shaped tumor, occupying $${}^3{/}_{\mathrm{four}}$$

intestinal lumen, leaving only part of the left wall free; Magnetic resonance imaging of the pelvic organs from August 18, 2014 at 95 mm from the internal sphincter determines a saucer-shaped tumor, up to 40 mm long, occupying 3/4 of the circumference of the rectum. It is difficult to assess the external contour at the level of education against the background of artifacts, however, there are strong suspicions of edge fiber infiltration on the right, the intestinal lumen is unevenly narrowed, patency is preserved. In pararectal tissue at the level of the upper and middle ampullar sections, as well as along the branches of the upper rectal artery, multiple lymph nodes up to 3-10 mm are determined. Own fascia at the educational level is not clearly defined.

In the period from 08/28/2014 to 09/26/2014, a course of remote gamma therapy in the multifraction mode of 1.3 Gy × 2 r / day 5 times a week was conducted against the background of capensitabine radiosensitization at a dose of 825 mg / m ² × 2 r / day and 10 sessions of local hyperthermia. No acute radiation reactions were observed.

The effectiveness of the treatment was evaluated 6 weeks after the end of the course of radiation therapy. The prevalence of the primary rectal tumor in this patient changed as follows: with fibrocolonoscopy on November 7, 2014, 12 cm from the Z-line, the intestinal lumen is deformed along the right wall due to erosion with a diameter of up to 1 cm with signs of scarring, with convergence of folds. Perifocal pattern of the mucosa is traced, ordered. Conclusion: Tumor of the rectum, condition after chemoradiotherapy, regression of the process; When magnetic resonance imaging of the pelvic organs from November 10, 2014, there is a zone of pathological amplification of diffusion, up to 12 mm long, the external contour of the intestine is clear throughout, there are no signs of the presence of an exorgan organ component. Pararectal fiber is swollen, along the branches of the upper rectal artery, single lymph nodes up to 2-3 mm are determined. In the pararectal cell, single lymph nodes up to 2-3 mm are determined.

The final stage of the combined treatment on November 26, 2014, performed an operation in the amount of transanal removal of the residual after neoadjuvant treatment of the tumor. The perioperative period was uneventful. Histology (surgical material): necrosis was noted in the part of the colon mucosa, in the preserved mucosa of the gland without atypia of the epithelium. Severe lymphoplasmacytic infiltration of the mucosa and muscle layers. No tumors were found, therapeutic pathomorphism of 4 degrees.

During the follow-up examination of April 2015, no data were found for relapse / progression of the disease.

This method treated 11 patients with colorectal cancer. At the stages of examination of patients after neoadjuvant chemoradiation treatment, 3 cases (27.3%) of complete, morphologically confirmed regression of the primary tumor were recorded; accordingly, these patients did not require a surgical treatment. In 8 clinical observations (72.7%), a partial regression of the tumor was achieved - the volume of the primary lesion decreased by more than 50%, which in 6 cases (54.5%) made it possible to perform a sphincter-saving operation. In all operated patients, the course of the postoperative period was favorable.

Thus, the proposed method allows to achieve a new technical result, namely to increase the effectiveness of treatment, to reduce the number of complications associated with radiation damage to tissues.

Information sources

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Claims (1)

A method for the combined treatment of locally advanced colorectal cancer, including preoperative remote radiation therapy with the introduction of chemotherapy and local hyperthermia, characterized in that the remote gamma therapy is carried out in a multifraction regimen of 1.3 Gy × 2 times a day, 5 days a week for 4 weeks of amid oral capecitabine in a dose of 825 mg / m ² × 2 times a day at intervals of 12 hours per days of radiotherapy, local hyperthermia is carried out on the background of chemoradiotherapy 3 times not Yeh-lii for 3 hours prior to irradiation session at a temperature of 42-44 ° C for 45-60 min for a total of 10 sessions.