RU2706346C1 - Method of treating operable gastric adenocarcinoma - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to treating gastric cancer. A method of treating operable gastric adenocarcinoma involves neoadjuvant chemotherapy involving Abraxane, 5-fluorouracil and oxaliplatin. Neoadjuvant chemotherapy is performed once, a catheter is inserted into the celiac, through which Abraxane, oxaliplatin and 5-fluoruracil are introduced infusion, wherein the Abraxane in amount of 50 mg/m² for an hour, oxaliplatin in amount of 50 mg/m² for 20 minutes and 1,000 mg/m² 5-fluorouracil for one hour, no earlier than two days after the chemotherapy is completed, surgical removal of the tumor, then no later than 4 weeks, adjuvant chemotherapy is administered by oral administration of capecitabine daily 2,500 mg/m² per day in 2 divided doses in the morning and in the evening, no more than 14 days, no more than once a month, implementing such introduction for not more than 4 months or until occurrence of undesired phenomena of II-III degree or progression of tumor process according to RECIST criteria.

EFFECT: invention provides treatment in a sparing mode, which makes it possible to use it in weakened patients, staying in hospital for 15–20 days.

1 cl, 1 ex

Description

The invention relates to medicine, more specifically to oncology, and may find application in the treatment of stomach cancer.

Adenocarcinoma is a type of stomach cancer (RJ) and an extremely aggressive malignant neoplasm with a negative statistical prognosis for both sexes around the world.

Stomach adenocarcinoma (AF) is one of the most common oncological diseases. According to domestic and foreign cancer registries, AF is the fourth most common form of cancer and the second leading cause of cancer death in the world. About 1 million new cases and more than 700 thousand deaths from this disease are recorded annually in the world.

The highest incidence rates are observed in Russia, Japan, Korea, China, Eastern Europe, East Asia and parts of Latin America, the lowest - in Australia, New Zealand and the USA (24 thousand new patients are registered annually in the USA).

Across the world, AF is more common in men than in women. So, in 2017, in the structure of oncological diseases in Russia, AF was 7.6% among men and 4.7% among women. Despite the fact that in recent years there has been a slight decrease in the number of patients with newly diagnosed cancer, in 2007 there were 41,941 new cases of AF, and by 2017 this figure was already 37,291. Mortality from AF in 2007 was 37,456 cases, and in 2017 - 28512. According to statistics, the improvement of treatment methods over the past decades has not led to an increase in patient survival. Despite the success of medicine in relation to other oncological diseases, in relation to AF practically no significant increase in the life expectancy of patients was achieved.

Russian and world statistics show that AF remains an unresolved problem of modern oncology and requires the search for new methods of treatment.

In accordance with modern clinical guidelines for the treatment of operable AF in both Russia and abroad, the main method remains surgical treatment in an adequate volume. The optimal operation can be considered as performed in the scope of gastrectomy, less often subtotal gastrectomy in combination with lymph node dissection D2. When performing surgical treatment in such a volume, the smallest number of local and locoregional relapses is noted.

In a number of cases, namely, in the presence of signs of damage to regional lymph nodes in the detection of low- and undifferentiated adenocarcinomas, perioperative chemotherapy is recommended.

Chemotherapy is carried out depending on the somatic state of the patient and the sensitivity of the tumor to chemotherapy. The standard is systemic chemotherapy in the neoadjuvant and adjuvant modes, with preference being given to regimens that include a combination of platinum preparations (oxaliplatin, cisplatin) and fluoropyrimidines (5-fluorouracil, capecitabine): CF, ECF, ECX, EOX, FLOT.

All recommended chemotherapy regimens are multicomponent, which leads to their toxicity and limits the use in weakened groups of patients.

To increase efficiency and reduce toxicity, a number of authors began to use intra-arterial chemotherapy in the treatment of gastric cancer from the 60s. It was first applied in 1957 [Arch. Surg. - 1957 - Vol. 74 - R. 516-524] with an inoperable tumor by introducing chemotherapeutic agents into the aorta at the site of cervical trunk discharge. Nevertheless, the authors did not find any advantages of such treatment. In other studies, after a femoral artery puncture, a catheter was brought to the mouth of the celiac artery and a chemotherapy (mitomycin-C) was introduced through it. Compared with the intravenous administration of chemotherapy, this gave a slight improvement in treatment outcomes. Subsequently, preoperative intra-arterial chemotherapy [Med. J. Aust. - Vol. 140 - p. 143-147. 1984 and Vol. 155 - p. 803-807. 1991]. The results of this treatment were stunning - four-year survival rate was 80%.

The most acceptable method of treatment at present is intra-arterial chemo-infusion, developed and used in the Federal State Budget Scientific Center of the Russian Chemistry Center. Acad. Granova A.M., which has long established itself as an effective method of treatment of many oncological diseases, including AF. Selective intra-arterial use of chemotherapy is one of the ways to increase the effectiveness of antitumor treatment. However, most modern chemotherapy drugs are not intended for intra-arterial (IV) administration. To date, 5-fluorouracil remains the only cytostatic approved for iv administration.

An analysis of domestic and foreign literature on X-ray endovascular studies in tumor therapy has shown great interest in the development and application of regional chemotherapy methods.

The interest of the researchers is due to the ability of the chemotherapy drug to penetrate and linger for a long time in the tumor tissue when it is introduced into the vessels supplying the tumors, significantly reducing the overall toxic effect on the body as a whole and thereby improving the quality of life of patients.

A known method of treating locally advanced cancer of the stomach with high metabolic and proliferative activity (RF Patent No.RU 2552289), comprising performing neoadjuvant regional chemotherapy using irinotecan in lipiodol followed by surgery. In this case, neoadjuvant regional chemotherapy is carried out by performing no more than two procedures of intra-arterial chemoembolization: the first is carried out by administering 1/2 of a single systemic dose of a chemotherapy drug in 4-6 ml of an oil X-ray contrast drug, and no later than 2-3 weeks, a control determination of tumor markers is carried out, PETUKT Ki-67 and SUVmax proliferation index and when at least one of these factors decreases compared with their initial values, the second procedure for intra-arterial chemoembolization is carried out they are produced by administration of not more than 1/3 of a single systemic dose of a chemotherapeutic drug in no more than 5 ml of an oil radiopaque drug.

A known method of treating malignant tumors of the stomach and duodenum (RF Patent No.RU 2436605) by intra-arterial administration of mitomycin-C, taxotere, 5-fluorouracil, gemzar, eloxatin in suspension with lipiodol.

The method consists in performing diagnostic angiography, identifying arteries feeding the zones of tumors of the stomach and / or duodenum, and chemotherapy drugs mitomycin-C, taxotere, 5-fluorouracil, gemzar, eloxatin are injected into these arteries in 0.5-1.0 ml lipiodol, and such treatment is carried out at least 1 time per month.

It should be noted that such chemotherapy has a fairly high toxic effect on the patient's body due to the greater number of antitumor drugs used, as well as due to repeated cycles of administration, therefore this scheme is not applicable in a weakened group of patients.

Nevertheless, these two methods compare favorably with the known ones due to the use of intra-arterial administration of chemotherapy drugs, which ensures a decrease in the overall toxic effect on the patient's body.

Closest to the proposed is a method of treating operable adenocarcinoma of the stomach using systemic chemotherapy with oxaliplatin, 5-fluorouracil and Nab-paclitaxel, described in Eur J Cancer. 2019 Jan 107: 46-52, which we have taken as a prototype.

This study describes the use in 49 patients of 6 cycles of systemic neoadjuvant chemotherapy with oxaliplatin 85 mg / m ² , 5-fluorouracil 2400 mg / m ² , leucovorin 400 mg / m ² and Nab-paclitaxel (abraxan) 150 mg / m ² standard treatment for operable adenocarcinoma of the stomach.

As noted by the authors of this work, despite the good effect achieved by such treatment, a serious drawback was the manifestation of toxic phenomena such as neph Febrile neutropenia (20.4%), nausea (8.2%), diarrhea (8.2%) and neuropathy (6.1%) due to the huge amount of neoadjuvant chemotherapy over 6 cycles, in our opinion, the number of chemotherapy drugs administered to the patient (510 mg / m ² oxaliplatin, 14400 mg / m ² 5-fluorouracil, 2400 mg / m ² leucovorin and 900 mg / m ² per course of treatment Abraxane), which significantly limits the widespread use of this method, especially , Debilitated patients.

In addition, the implementation of 6 cycles of neoadjuvant chemotherapy, requiring a long stay of patients in clinical conditions, significantly lengthens the duration of treatment.

The technical result of the present invention consists in reducing the length of hospital stay of patients, reducing the number of chemotherapy drugs administered to them and reducing the overall toxic effect on the body through regional chemotherapy and optimization of the treatment process.

This result is achieved by the fact that in the known method of treating operable AF including neoadjuvant chemotherapy using abraxan, 5-fluorouracil and oxaliplatin, according to the invention, neoadjuvant chemotherapy is performed once, while a catheter is inserted into the celiac trunk through which abraxan, 5-oxaliplatin fluorouracil is administered by infusion, with Abraxane at 50 mg / m ² administered within an hour, oxaliplatin at 50 mg / m ² for 20 minutes and 1000 mg / m ² of 5-fluorouracil for one hour, not previously h m two days after the end of chemotherapy performed surgical removal of the tumor, followed by no later than 4 weeks operate adjuvant chemotherapy through oral capecitabine daily 2500 mg / m ² per day in 2 divided doses, morning and evening not more than 14 days, no more than once per month carrying out such an introduction no more than 4 months or until the appearance of adverse events of the II-III degree or the progression of the tumor process according to the RECIST criteria.

Our use of regional intra-arterial (IV) chemotherapy, in which about 50% of the chemotherapy remains in the tumor node, provides a significant reduction in the overall toxic effect on the patient's body by delivering the chemotherapy to the tumor directly through the vessel supplying it, which improves the quality of life for patients. Moreover, due to the “first passage” of the drug and a significant increase in its concentration around the neoplasm, the greatest effect is achieved, which reduces the duration of treatment of the patient, his stay in the clinic and reduces the overall toxic effect of chemotherapy.

In this regard, the use of oxaliplatin in an amount of 50 mg / m ² , which corresponds to a dose reduction of 40% of the system dosage, as well as abraxan in an amount of 50 mg / m ² (recommended dose of 125 mg / m ² ) and 1000 mg / m ² 5-fluorouracil and thus a significant reduction in the total amount of chemotherapy drugs administered to the patient per treatment course (in particular, oxaliplatin and abraxan almost ten times) due to regional administration, they provide a sparing treatment regimen, which makes the method suitable for treating debilitated patients. In addition, the regional administration of abraxan as the last generation chemotherapeutic agent allows us to achieve a high antitumor effect in the amount claimed by us, while ensuring a low level of general toxicity.

In recent years, this new generation chemotherapy has been finding wider application for the treatment of various neoplasms, and therefore we have used it in our treatment regimen for gastric adenocacinoma in the regimes we offer. The drug is practically insoluble in water, therefore, for clinical use, a special dosage form was developed - taxol, which is a concentrate of paclitaxel, dissolved in a mixture of polyoxyethylated castor oil (Cremophor EL with ethanol). The choice of solvent was forced to a certain extent, since it causes acute hypersensitivity reactions and enhances the toxic effect of paclitaxel. To overcome toxic reactions, a system of preventive measures was developed. When carrying out intravenous infusions of Taxol, the use of special systems of polypropylene or polyolefin was required, because cremophor is able to flush plasticizer from plasticized polyvinyl chloride into the blood, from which standard infusion systems are made. In experimental studies it was shown that this plasticizer is very toxic, has carcinogenic properties, cardiopulmonary toxicity, hepato and nephrotoxicity. All of the above properties of taxol do not allow its use as a drug for regional v / a administration.

To overcome these negative aspects, in 2014, a new form of paclitaxel stabilized by albumin was developed, called Abraksan. It is an ordinary, unmodified paclitaxel in the form of nanoparticles obtained by special processing of a mixture of paclitaxel with human albumin. Diluting the drug with water produces a suspension suitable for intravenous administration. The good solubility of abraxan in water can reduce the duration of infusion to 30 minutes instead of 3 hours in the treatment of taxol. The mechanism of action of abraxan is similar to the action in the form of taxol.

Researchers' interest is due to the ability of the drug to penetrate and linger for a long time in the tumor tissue when it is introduced into the vessels of the tumors, showing diagnostic efficacy and, in some cases, an antitumor effect.

The use of 5-fluorouracil in the scheme of our method of treatment is due to its known low toxicity and satisfactory tolerance by patients, and, like the above drugs, it is administered to patients in an amount more than 10 times less than the course of treatment than in the known methods.

Surgical removal of the tumor no earlier than two days after the end of regional chemotherapy provides optimal conditions for the surgical operation, namely the absence of pronounced post-ebolization changes in the form of a significant adhesion process and fibrotic tissue changes in the area of surgical intervention, while the positive effects of chemotherapy due to a sufficiently long delay in chemotherapy in the tumor tissue - in the form of a decrease in the metabolic activity of the tumor, reduced ia tumor mass, which increases the ablasticity of surgical treatment.

And further chemotherapy by oral administration of capecitabine in an amount of 2500 mg / m ² 2 times a day in the morning and in the evening no more than 14 days no more than once a month with the introduction of such administration no more than 4 months or until the appearance of adverse events of II-III degree or the progression of the tumor process according to the RECIST criteria consolidates the achieved positive effect, providing an even greater strengthening of the chemotherapeutic treatment we are performing.

The proposed method for the treatment of operable AF, developed and tested by us under clinical conditions, allowed us to achieve disease control, reduce pain and, as a result, improve the quality of life of patients. A significant reduction in the doses of the chemotherapy used ensured that these drugs had a gentle effect on the patient’s body and, as a result of their satisfactory tolerance, made it possible to carry out the entire treatment regimen without interruption, including in debilitated patients. Since the claimed method is new, nevertheless, which has passed clinical testing to date in 6 patients with achieving positive results, we do not have long-term long-term results, but we have received encouraging positive results with a satisfactory quality of life for patients treated in this way during and after the course of treatment allows us to hope to maintain the results achieved in the future. In our opinion, the results obtained with satisfactory tolerance of treatment by patients allow us to recommend such a gentle method for use in groups of weakened patients ECOG P.

The essence of the method is illustrated by examples.

EXAMPLE 1

Patient K., 70 years old. He was admitted to the clinic of the Federal State Budget Scientific Center of the Russian Science and Cardiology Center of the Ministry of Health of the Russian Federation on 05.17.2019 with a diagnosis of T3N2M0 stage 3a adenocarcinoma of the subcardial stomach.

From the anamnesis: Considers herself ill since April 2019, when a single, plentiful black stool appeared, was hospitalized in a surgical hospital. According to fibrogastroduodenoscopy with a biopsy dated 04/10/19, the formation of the cardial part of the stomach is closer to the lesser curvature 2.5 × 1.5 cm in size. The histological conclusion is a low-differentiated adenocarcinoma. According to computed tomography of the abdominal cavity from 04/16/19 - multiple enlarged lymph nodes from 12 to 23 mm were determined by the lesser curvature of the stomach. According to positron emission tomography combined with computed tomography with 18F fluorodeoxyglucose from 04.25.19 - pathological accumulation of a radiopharmaceutical in the gastrohepatic ligament region, conglomerate size up to 5.3 cm. Neoplasm in the stomach with increased accumulation of radiopharmaceuticals up to 2.3 cm. The patient was referred for consultation at the Russian Science Center RCH for further examination and treatment.

On admission to the RSC on May 17, 2019, complaints of moderate pain in the epigastric region. Objectively: satisfactory condition, height -176 cm, weight 58 kg; body surface area (PPT) = 1.68 m ²

The skin is clean, the lymph nodes are not enlarged. Borders of the heart are within normal limits, heart rate (HR) 80 beats / min, heart sounds are clear, rhythmic. The chest is regular in shape, symmetrically involved in breathing, hard breathing, no wheezing. The abdomen is soft, painless, the liver at the edge of the costal arch, the spleen is not enlarged. The kidneys are not palpable. Physiological administration unchanged.

The patient was hospitalized for combined treatment in the amount of intraarterial chemotherapy for a stomach tumor and subsequent possible surgical treatment.

The results of the examination before the procedure: Clinical blood test from 05/20/2019: Hemoglobin 103 g / l, Red blood cells 3.48 × 10 ¹² / L, platelets 313 × 10 ⁹ / L, White blood cells 3.68 × 10 ⁹ / L, Neutrophils 46.4%, Lymphocytes 32.1%, Monocytes 15.2%, Eosinophils 6%, Basophils 0.3%.

Blood biochemical analysis dated 05/20/2019: glucose 4.89 mmol / l, total protein 63 g / l, total bilirubin 8.6 μmol / l, ALT 11 units / liter, ACT 19 units / liter, amylase 89 units / liter.

May 21, 2019 - Diagnostic angiography. Upper mesentericography. Celiacography.

Under angiooperative conditions, under local anesthesia with 20 ml of a 1% solution of novocaine, the right femoral artery was punctured according to Seldinger. The Hook 5 F catheter is installed in the celiac trunk.

On angiograms, the vascular anatomy of the hepatopancreatobiliary zone is typical. Usuations of the common hepatic, splenic and superior mesenteric arteries were not found. The left gastric artery is passable throughout, the right was not visualized. In the projection of the middle third of the stomach there are signs of a pathological formation with tumor vessels. The portal vein is passable throughout.

Conclusion: malignant neoplasm of the stomach

After diagnostic angiography dated 05/21/2019, an aqueous solution of 84 mg (50 mg / m ² ) of Abraxan was administered infusion over an hour, 84 mg (50 mg / m ² ) of oxaliplatin for 20 minutes and 1680 mg through a catheter inserted into the celiac trunk. (1000 mg / m ² ) 5-fluorouracil for an hour. To obtain a solution of abraxan, it was dissolved in 10 ml of physiological solution, a solution of oxaliplatin in 50 ml of a 5% glucose solution, mixing it with it immediately before administration. A solution of 5-fluorouracil was also prepared immediately before its administration.

The procedure was transferred without features. After completion of intra-arterial chemoinfusion, the arterial catheter was removed, a pressure bandage was applied to the area of the femoral artery puncture. The patient was immobilized for 8 hours after the removal of the arterial catheter. The treatment was transferred without features.

Clinical blood test dated 05.22.2019: Hemoglobin 106 g / l, Red blood cells 3.52 × 10 ¹² / L, platelets 230 × 10 ⁹ / L, White blood cells 3.55 × 10 ⁹ / L, Neutrophils 41.9%, Lymphocytes 30 , 7%, Monocytes 16.9%, Eosinophils 9.9%, Basophils 0.6%.

Biochemical analysis of blood from 05.22.2019: glucose 4.62 mmol / L, total protein 62 g / L, total bilirubin 6.1 μmol / L, ALT 17 U / L, ACT 22 U / L, amylase 35 U / L.

05.24.2018 operation. Laparotomy Extirpation of the stomach. Lymphatic dissection.

Histological examination dated 05/31/2019: gastric adenocarcinoma Conservative therapy was carried out: infusion, symptomatic, antisecretory antibacterial, hepatotropic, replacement therapy. The postoperative period without features.

Clinical blood test dated 05/31/2019: Hemoglobin 123 g / l, red blood cells 4.11 × 10 ¹² / l, platelets 327 × 10 ⁹ / l, white blood cells 5.85 × 10 ⁹ / l, neutrophils 60.1%, lymphocytes 17 , 3%, Monocytes 10.8%, Eosinophils 11.8%, Basophils 0%.

Blood biochemical analysis dated 05/31/2019: glucose 5.54 mmol / l, total protein 58 g / l, total bilirubin 6.8 μmol / l, ALT 22 units / liter, ACT 24 units / liter, amylase 35 units / liter.

Given the satisfactory condition of the patient during neoadjuvant chemotherapy in a gentle mode and in the postoperative period, the patient was discharged from the clinic on June 04, 2019 in satisfactory condition under the supervision of a district oncologist, with recommendations for oral administration of capecitabine daily 2500 mg / m ² per day in 2 doses in the morning and evening no more than 14 days, no more than once a month, no more than 4 months or until the appearance of adverse events.

The patient’s stay in the clinic of the Russian Science Center RHT was 18 days.

From 10.06.2019 to 24.06.2019, for 14 days, oral administration of capecitabine in the amount of 4200 mg (2500 mg / m ² ) per day in 2 doses (in the morning -2200 mg and in the evening - 2000 mg). Moved treatment without features.

From 08.07.2019, repeated oral administration of capecitabine in the previous regimen.

Currently, the patient's condition is satisfactory, oral administration of capecitabine continues. Surveillance at the place of residence.

Our sparing regional polychemotherapy allowed us to achieve good tolerance indicators while maintaining the stabilization of the disease in accordance with the RECIST criteria. Clinically noted a positive effect in the form of a decrease in pain. The patient's condition during the entire course of treatment remained and is still satisfactory.

To date, the proposed method has treated 5 patients with a reduction in the overall toxic effect due to regional administration and a reduction in the dose of chemotherapy drugs, and the use of such sparing chemotherapy regimens has allowed treatment in a weakened group of patients, which distinguishes our method from the known ones.

The hospital stay of patients was 15–20 calendar days, while treatment with neoadjuvant systemic chemotherapy and subsequent surgical removal of the tumor was at least 30–35 calendar days. Moreover, the number of chemotherapy drugs used to treat patients is significantly reduced due to their regional administration.

Due to the fact that the proposed method is new, unfortunately, we do not yet have long-term results of treatment, but the satisfactory condition of all the patients treated by us and the sparing regimes of performing the stages of treatment allows us to hope to maintain the achieved results in the future.

The method is developed in the Department of Operative Surgery No. 2 of the Academician Granov A.M. and underwent clinical testing in 5 patients with a positive result.

Claims (1)

A method of treating operable adenocarcinoma of the stomach, including neoadjuvant chemotherapy using abraxan, 5-fluorouracil and oxaliplatin, characterized in that neoadjuvant chemotherapy is performed once, while a catheter is inserted into the celiac trunk through which abraxan, oxaliplatin and 5 are injected with this drug and 5 abraxan in an amount of 50 mg / m ² for an hour, oxaliplatin in an amount of 50 mg / m ² for 20 minutes and 1000 mg / m ^{2 of} 5-fluorouracil for one hour, not earlier than two days after the end chemotherapy involves surgical removal of the tumor, then adjuvant chemotherapy is performed by oral administration of capecitabine daily 2500 mg / m ² per day in 2 doses in the morning and evening for no more than 14 days no more than once a month, no more than 4 months or until the appearance of adverse events of the II-III degree, or the progression of the tumor process according to the RECIST criteria.