RU2678642C1 - Method of modified chemical treatment of colorectal cancer - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to medicine, namely to oncology, and can be used for the modified chemoradiation treatment of colorectal cancer. To do this, perform the catheterization of the upper rectal artery through the femoral artery, into which cisplatin 50 mg is injected on 5 % glucose 50 ml and fluorouracil 500 mg within 30 minutes. From the next day, a short course of large-fractional radiation therapy is carried out – 5 sessions of 5 Gy per primary tumor and regional lymph nodes. Before the start of each radiotherapy session, 100 ml of ozonized physiological saline with an ozone concentration of 1,000 mcg/l are administered intravenously over 10 minutes, after 5 minutes, fluorouracil 500 mg is injected in a solution of sodium chloride 0.9 %, 200 ml within 30 minutes. After a 30-minute exposure, a radiotherapy session is performed. 4 weeks after the end of the course of the modified chemoradiation treatment of colorectal cancer, an operative intervention on the rectum is performed – resection or extirpation of the rectum in a standard volume.EFFECT: method provides an increase in efficiency and a decrease in the duration of treatment while improving its results.1 cl, 2 ex

Description

The invention relates to medicine, namely to oncology, and can be used to determine the optimal duration of surgery after prolonged radiation therapy for colorectal cancer to individualize and select the optimal treatment tactics.

Radiation therapy has now become the standard in the combined treatment of colorectal cancer. Moreover, of the existing types of radiation therapy (pre- and postoperative), it is preoperative radiation therapy that has gained the most recognition and distribution.

In the United States, from 2004 to 2011, the proportion of patients who received neoadjuvant radiation therapy increased from 57 to 75%, and the proportion of patients who received postoperative radiation therapy, on the contrary, decreased from 39 to 18% (see Abrams MJ The Emerging Non- Operative Management of Non-metastatic Rectal Cancer: A population Analysis / MJ The Emerging Non-operative Management of Non-metastatic Rectal Cancer: A Population Analysis / MJ Abrams, PP Koffer, KL. Leonard et al. // Anticancer Res. - 2016 - Vol. 36. - N4 - P. 1699-1702). The same trends are noted in European countries and in Russia.

Neoadjuvant prolonged radiation therapy can halve the 5-year relapse rate for colorectal cancer from 10.9 to 5.6% (see Peeters K.C., Marijnen S.A., Nagtegaal I. Detal. The TME trial after a median follow-up jf 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann. Surg. 2007; 246: 693; see Ferrari L. Neoadjuvant chemoradiation therapy and pathological complete response in rectal cancer / L. Ferrari, A. Fichera // Gastroenterol Rep (Oxf) -2015 Vol. 3. - No. 4 - P. 277-88).

In large randomized trials of SRCSG and SRCT, in addition to reducing the frequency of local relapses, an increase of 10% in the relapse-free and overall survival of patients was revealed.

However, the problem is that prolonged radiation therapy takes about 5 weeks, then an interval of 8 weeks is required before surgical treatment. This delays the implementation of surgery for 13 weeks, at which time the tumor may progress in case of low sensitivity of the tumor to radiation treatment. The way out of this situation could be the use of a short course of radiation therapy, but with it there is no tumor regression.

In this regard, the search for ways to increase the effectiveness of a short course of radiation therapy, which will reduce the duration and cost of treatment, is currently relevant.

The well-known "Method of neoadjuvant chemotherapy for colorectal cancer" (see Rasulov A.O., Gordeev S.S., Ivanov V.A., Barsukov Yu.A., Malikhov A.G., Baychorov A.B., Tkachev S .I., Kozak EN A short course of preoperative radiation therapy in combination with chemotherapy, local hyperthermia and a prolonged interval before surgery in the treatment of colorectal cancer: phase II study. ”Oncological coloproctology. No. 4. 2016. P. 24-30 ) The method includes a short course of radiation therapy with SOD 25 Gy of 5 Gy while taking capecitabine (1000 mg / m ² 2 times a day for 1-14 days), metronidazole (in the composition of the polymer composition at a dose of 10 g / m rectally at 3 and 5 days ) and local hyperthermia (for 60 minutes at a temperature of 41-45 ° C for 3-5 days. Surgical treatment was performed no earlier than 4 weeks after the end of neoadjuvant treatment.

However, in 48.1% of patients with the use of this method toxic phenomena occurred, and local radiation reactions and complications were not analyzed. Oncological treatment results are only comparable with a prolonged course of radiation therapy, but do not exceed it. Therapeutic pathomorphism of 3-4 degrees developed only in 47.5% of patients. 12.3% of patients with a median follow-up of 40.9 months developed distant metastases. These data indicate the need for a further search for ways to increase the effectiveness of a short course of radiation therapy.

The well-known "Method for the combined treatment of cancer of the left half of the colon and the upper ampullar region of the rectum" (see RF patent for the invention No. 2358660, 2009, BIPM No. 17), including embolization of the artery that feeds the tumor, a composition based on the drug oxaliplatin, followed by surgery . For this purpose, selective catheterization of the inferior mesenteric artery was performed using Seldinger femoral access, then super-selective catheterization of the left colon, sigmoid or superior rectal artery was performed. Then, an emulsion of 50-100 mg of oxaliplatin was introduced in an oil contrast preparation (super-liquid lipiodol 3-10 ml). Next, mechanical occlusion of the vessels supplying the tumor was performed using a hemostatic sponge, metal spirals. 3-5 days after tumor embolization, radical surgery was performed.

The disadvantages of this method are the absence of the effect of preoperative tumor devitalization, as well as a short exposure to chemotherapy, since the oil embolizate did not accumulate the chemotherapy and did not lead to complete occlusion of the vascular bed, which reduced the duration of the chemotherapy treatment on the tumor and also increased the likelihood of metastasis.

The well-known "Method of combined treatment of colorectal cancer" (see RF patent for the invention No. 2269341, 2006, BIPM No. 4), selected by us as a prototype. The method involves local radiomodification by endovascular perfusion with a 5% solution of metronidazole through the superior rectal artery for cancer of the upper ampulla of the rectum and one of the internal iliac arteries for cancer of the middle and lower ampulla of the rectum with occlusion of these vessels by radiopaque emboli. A single remote radiation therapy with a dose of 10 Gy was performed 1 hour after radiomodification. The operation was carried out no more than 24 hours after irradiation.

The disadvantage of this method was the presence of possible complications of radiation therapy, manifested in the form of skin reactions, leukopenia, thrombocytopenia, anemia, an increased risk of intestinal anastomosis failure. Radiation exposure had a negative effect on the viability of the anal sphincter. The metal spirals used as emboli did not provide sufficient tumor devitalization and did not improve the quality of chemotherapy on the tumor tissue.

The technical result of our invention is to increase the effectiveness of a short course of radiation therapy for colorectal cancer by modifying to individualize tactics and improve treatment outcomes of patients.

The technical result is achieved by the fact that patients perform catheterization of the upper rectal artery through the femoral artery, into which cisplatin 50 mg with 5% glucose 50 ml and fluorouracil 500 mg are administered for 30 minutes, from the next day the patients are given a short course of coarse radiation therapy - 5 sessions 5 Gy per primary tumor and regional lymph nodes, before the start of each radiation therapy session, 100 ml of ozonized physiological saline solution is injected intravenously - ozone concentration - 1000 μg / l for 10 minutes, after 5 minutes fluorouracil 500 mg is introduced in a solution of sodium chloride 0.9% 200 ml for 30 minutes, after a 30-minute exposure, a radiotherapy session is performed, surgery on the rectum - resection or extirpation of the rectum in a standard volume is performed 4 weeks after the end of the course modified chemoradiotherapy for colorectal cancer.

The invention, “A method for modified chemoradiation treatment of colorectal cancer,” is new, as it is unknown in the field of medicine in the combined treatment of resectable colorectal cancer, during preoperative radiation therapy.

The novelty of the invention lies in the fact that patients with colorectal cancer, who are shown to undergo radiation therapy as the first stage of treatment, catheterize the upper rectal artery through the femoral artery, into which cisplatin 50 mg with 5% glucose 50 ml and fluorouracil 500 mg are administered for 30 minutes ; from the next day, a short course of coarse radiation therapy is administered to patients (5 sessions of 5 Gy per primary tumor and regional lymph nodes), 100 ml of ozonized physiological saline (ozone concentration - 1000 μg / l) is injected intravenously before each treatment session (10 oz) minutes, after 5 minutes, fluorouracil 500 mg is introduced in a solution of sodium chloride 0.9% 200 ml for 30 minutes; after a 30-minute exposure, a radiation therapy session is performed; surgery on the rectum (resection or extirpation of the rectum in a standard volume) is performed 4 weeks after the end of the course of modified chemoradiation treatment of colorectal cancer.

Thus, the modification of radiation therapy for colorectal cancer contributes to the individualization of treatment tactics, increase efficiency, reduce treatment time, and, as a result, improve the results of treatment of patients with colorectal cancer.

The method is as follows.

A patient with colorectal cancer, who is shown to undergo radiation therapy as the first stage of treatment, catheters the upper rectal artery through the femoral artery into which cisplatin 50 mg with 5% glucose 50 ml and fluorouracil 500 mg are injected. From the next day, a short course of coarse radiation therapy is given to patients (5 sessions of 5 Gy per primary tumor and regional lymph nodes), 100 ml of ozonized physiological saline solution (ozone concentration - 1000 μg / l) is injected intravenously before each radiation therapy session (10 sessions) minutes, after 5 min, fluorouracil 500 mg is introduced in a solution of sodium chloride 0.9% 200 ml for 30 minutes. After a 30-minute exposure, a radiation therapy session is performed. Surgery on the rectum (resection or extirpation of the rectum in a standard volume) is performed 4 weeks after the end of the course of modified chemoradiation treatment of colorectal cancer.

The invention, “A method for the modified chemoradiation treatment of colorectal cancer,” is industrially applicable, as it can be used in medical institutions of oncological profile, dispensaries, and oncological research institutes.

We present clinical examples of the application of the "Method of modified chemoradiotherapy of colorectal cancer."

Example No. 1.

Patient B., born in 1956, was admitted to the clinic of the Federal State Budgetary Institution “RNII” of the Ministry of Health of the Russian Federation on 03.02.2017 with complaints of blood and mucus in the feces, tenesmus, weakness.

From the anamnesis it is known that he considers himself sick since December 2016, when the above complaints appeared. I went to the doctor at the place of residence, with FCC revealed a tumor of the rectum (protocol not shown). Histoanalysis: G2 adenocarcinoma. The patient was sent to RNII. On examination:

CRT of OGK 01.20.2017: there is no tumor in the lungs and mediastinum

MRI OBP, OMT 01/25/2017: tumor of the middle ampullar part of the rectum with spread to the upper ampullar part 7.5 × 2.4 × 4.3 cm, at a distance of 8.1 cm from the anus, with lesion of mesorectal lymph nodes.

FCC 12/28/16: a tumor of the rectum 10 cm from the anus, examination to the cecum. Histological examination (revision): G2 adenocarcinoma.

With a diagnosis of (C20) colorectal cancer cT3N1M0, st 3, gr 2 was hospitalized for treatment.

02/07/2017, the upper rectal artery was catheterized through the femoral artery, into which cisplatin 50 mg was introduced with 5% glucose 50 ml and fluorouracil 500 mg. 02/08/2017, the patient began a short course of coarse radiation therapy (5 sessions of 5 Gy for the primary tumor and regional lymph nodes), before the start of each radiation therapy session, 100 ml of ozonized physiological saline solution (ozone concentration - 1000 μg / l) was administered within 10 minutes, after 5 minutes, fluorouracil 500 mg was introduced in a solution of sodium chloride 0.9% 200 ml for 30 minutes. After a 30-minute exposure, a radiation therapy session was conducted.

The course of the modified chemoradiation treatment was satisfactory, there were no reactions and complications.

During the control examination:

RRS 03/13/2017: ulceration of the mucosa up to 3 cm in diameter at 8 cm from the anus.

MRI of the organs of the abdominal cavity and small pelvis 03/13/17: a tumor of the middle ampulla of the rectum with signs of pathomorphosis; Uenenie volume of metastatic lesion of mesorectal lymph nodes in dynamics

03/15/2017 surgery performed anterior resection of the rectum.

Macro drug: at the site of the tumor - ulceration of the rectal mucosa up to 3 cm in diameter. Regional lymph nodes are not changed.

Postoperative histoanalysis: G2 adenocarcinoma with invasion of all layers of the wall, ulceration, inflammation. Signs of therapeutic pathomorphism are petrificates in the fibrous stroma; resection lines have the usual structure ;: in the lymph nodes, sinus histiocytosis, focal lipomatosis.

The postoperative period was uneventful, without complications.

Thus, the given clinical example demonstrates a pronounced regression of the rectal tumor in a short time under the influence of modified radiation therapy: the tumor from 7.5 cm decreased to ulceration of the mucosa with a diameter of 3 cm. These data indicate the high efficiency of the developed “Method of modified chemoradiotherapy of rectal cancer ".

Example No. 2

Patient P., born in 1951, was admitted to the clinic of the Federal State Budgetary Institution "RNII" of the Ministry of Health of the Russian Federation on 02.11.2016 with complaints of weakness, bloating, tenesmus up to 6-7 times a day, an admixture of blood and mucus in the feces.

From the anamnesis it is known that he considers himself ill from the spring of 2016, when constipation appeared and increased (up to 3-4 days), bloating, took laxatives, from July 2016 an admixture of blood and mucus in the feces after defecation, frequent "False" urge to defecate up to 6-7 times a day, in small portions. He went to the oncologist at the place of residence, a rectal tumor was diagnosed and verified. Sent to RNII, where he was comprehensively examined.

Sigmoidoscopy from September 21, 2016. The tube was inserted to a depth of 13 cm, the tone of the intestinal wall was normal, the mucous membrane was pink throughout, the mucous membrane was purple-red by 10-13 cm, it was loosened, bloody, “overgrown”, a biopsy. Conclusion: a tumor of the middle and upper ampullar part of the rectum.

Histological analysis of the biopsy specimen with RRS 09/21/16 .: highly and moderately differentiated rectal adenocarcinoma.

Revision of the CD disk of SRKT OBP and OGK from 10/03/2016. Pulmonary tissue without foci, pneumofibrosis. The liver is without foci, the structure is heterogeneous. In the projection of the rectum, compaction and thickening of the mucosa up to 2.0 cm, in the interval up to 3-4 cm (regional l / y up to 1.2 cm).

MRI of OBP and OMT from 10/25/2016 g MP picture of a circular solid tumor process of the wall of the middle and upper ampullar sections of the rectum with invasion of pararectal tissue. The wall of the organ is unevenly thickened, circular, infiltrated by a solid formation, its size is 28 × 35 × 25 mm, the muscle layer of the middle-upper ampullar sections is infiltrated extensively, is clearly differentiated in the area of tumor infiltration, signs of tumor growth in the cellulose at the level of acetabulum, to a depth of 4 mm, a l / a mesorectal collector up to 6 × 7 mm, suspicious of metastatic lesion) was detected).

FCC from 10.25.2016 in the rectum - a circular ulcerated tumor with raised edges and clear boundaries, with a lower edge 10 cm of the length of the endoscope from the anus, the lumen narrows to 15 cm to 7-8 mm, we do not pass with the endoscope.

Conclusion: saucer-like tumor of the upper ampullar part of the rectum, subcompensated stenosis.

The diagnosis was made: (C20) cancer of the upper and middle ampullar part of the rectum cT3NxM0, st 2, gr 2.

From 02.11.16 to 10.11.16, a short course of coarse-grained DHT was carried out on the primary tumor and zones of lymph outflow of 5 Gy, SOD 25 Gy.

During the control examination:

MRI of OBP and OMT from 11/12/2016 g MP picture of a circular solid tumor process of the wall of the middle and upper ampullar sections of the rectum. The size of the tumor is 48 × 45 × 35 mm, the tumor sprouts all layers of the intestinal wall, mesorectal lymph nodes up to 5 mm.

11/15/2016 operation low anterior resection of the rectum with the formation of a lateral reservoir-rectal anastomosis, preventive ileostomy.

Description of the macrodrug: a rectal tumor up to 5 cm in diameter, saucer-like, sweaty, regional lymph nodes up to 6 mm, elastic.

Postoperative histoanalysis dated 11/15/2016: G2 adenocarcinoma, invasion of all layers; no tumor along the lines of resection; in 12 lymph nodes there are no metastases.

The postoperative period was uneventful, without complications.

Thus, the given clinical example demonstrates the absence of pronounced regression of the rectal tumor with a short course of preoperative radiation therapy: the tumor did not decrease in size. These data indicate the need for modification to achieve tumor regression.

Under our supervision, there were 18 patients with resectable rectal cancer from 52 to 68 years old who were undergoing treatment at the clinic of the Federal State Budget Scientific Institution RNII of the Ministry of Health of the Russian Federation. The diagnosis was verified in all cases.

All patients were shown a preoperative short course of radiation therapy. 10 patients underwent standard preoperative radiation therapy with a short course without modification (control group), 8 patients received the developed “Method of modified chemoradiotherapy of colorectal cancer” (main group).

The results of the study showed that in the control group of patients for a short course of preoperative radiation therapy without modification the tumor regression does not have time to develop, although a histological examination of the removed tumor reveals therapeutic pathomorphosis of 1-2 degrees.

When using the developed “Method of modified chemoradiotherapy of colorectal cancer” (the main group of patients), a pronounced regression of the tumor is observed: at the site of the tumor in the postoperative preparation, ulceration of the mucosa is determined in all patients (therapeutic pathomorphosis of 3-4 degrees).

Patients were monitored for 2 years after treatment; tumor progression was not detected in the main group of patients. In the control group, 1 patient had a local tumor recurrence 14 months after treatment (10%), another patient developed distant metastases (10%).

The technical and economic effectiveness of the “Method of modified chemoradiotherapy of colorectal cancer” lies in the fact that the use of the method allows for a short period of treatment to significantly increase its effectiveness, individualize treatment tactics, improve the results of treatment of patients with colorectal cancer, is simple to implement. The method will reduce the cost of treating colorectal cancer by increasing its effectiveness and decreasing the duration.

Claims (1)

A method for the modified chemoradiation treatment of colorectal cancer, including short-course preoperative radiation therapy with large dose fractionation, characterized in that the patients catheterize the superior rectal artery through the femoral artery into which cisplatin 50 mg with 5% glucose 50 ml and fluorouracil 500 mg are administered 30 minutes, from the next day, patients are given a short course of large-fraction radiation therapy - 5 sessions of 5 Gy per primary tumor and regional lymph nodes, before the start of each radiation tera session FDI is injected intravenously with 100 ml of ozonized physiological solution - ozone concentration of 1000 μg / l - for 10 minutes, after 5 minutes, fluorouracil 500 mg is introduced in a solution of sodium chloride 0.9% 200 ml for 30 minutes, after a 30-minute exposure a radiation therapy session, surgery on the rectum - resection or extirpation of the rectum in a standard volume - is performed 4 weeks after the end of the course of modified chemoradiation treatment of colorectal cancer.