RU2712302C1 - Method of treating operable adenocarcinoma of duodenum - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to oncology, and can be used for treating operable duodenum adenocarcinoma. Method involves surgical removal of the tumor and chemotherapy. No earlier than two days before surgical removal, neoadjuvant chemotherapy is performed by intra-arterial bolus administration of 50 mg/m² abraxane in its suspension in no more than 3 ml of lipidol through a catheter inserted into a gastroduodenal artery. Catheter is then reinserted into celiac and 5-fluorouracil is introduced in amount of 1,000 mg/m² for one hour and additionally 50 mg/m² oxaliplatin for 30 minutes. Thereafter, no later than 4 weeks after surgical removal of the tumor, adjuvant chemotherapy with capecitabine is administered orally daily at 2,500 mg/m² per day in 2 doses in the morning and in the evening for no more than 14 days, while taking capecitabine once a month for not more than 4 months.

EFFECT: method provides reduced total toxic effect on patient's body due to regional administration of chemopreparations.

1 cl, 1 ex

Description

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

The main types of duodenal cancer (RDC) are adenocarcinoma, neuroendocrine tumors, lymphomas, and gastrointestinal stromal tumors. The first two species are the most common, with the most aggressive duodenal tumor being an adenocarcinoma.

Duodenal adenocarcinoma (ADC) accounts for less than 1% of all cases of gastrointestinal cancer. Given the low percentage of this disease, in the literature the amount of information about its treatment is extremely limited.

Differential diagnosis of ADC requires a thorough histopathological examination. In this case, cancer of the stomach, pancreas, and distal bile duct must be excluded.

The main treatment for such tumors is surgical. The prognosis of patients with operable ADC is determined, first of all, by the stage of the disease, but, unfortunately, the early stages are extremely rarely diagnosed. As you know, such tumors metastasize to the lymph nodes, and therefore the long-term results of only surgical treatment remain extremely unsatisfactory. One of the ways to solve this problem is combined treatment, namely the combination of surgery with drug antitumor chemotherapy in both neoadjuvant and adjuvant modes.

Closest to the proposed method is the treatment of operable ADC described in the work “Outcomes and Treatment Options for Duodenal Adenocarcinoma A Systematic Review and Meta-Analysis” Ann Surg Oncol (2018) 25: 2681-2692, which we took as a prototype.

In this paper, the authors summarize the published results of 26 studies on the treatment of ADC. The study included 6438 patients.

The main and more common methods for the treatment of ADK, according to the authors, are surgical removal of the tumor in combination with intravenous and oral systemic neoadjuvant, adjuvant chemo and radiation therapy.

1028 patients underwent combined treatment using surgical removal of the tumor, intravenous systemic chemotherapy and radiation therapy. An analysis of this study showed that radiation therapy does not have a significant effect on improving the long-term survival of patients with ADC.

Five studies, which included 117 patients, were devoted to studying the effect of intravenous systemic neoadjuvant chemotherapy, but no improvement in patient survival was obtained.

After analyzing the results of the treatment of ADC published in this work, we came to the conclusion that the existing antitumor efficacy of the existing combination treatment protocols using monochemotherapy regimens is low, as well as the lack of optimal modern methods of neo- and adjuvant systemic chemotherapy.

According to several authors, a significant factor in the poor prognosis of ADC is a metastatic lesion of the regional lymph nodes, which is a significant factor in reducing the long-term survival of patients.

It has also been proved that treatment regimens for ADK using intravenous systemic chemotherapy are highly toxic and can be used in a limited number of patients, due to the low general status of patients due to the underlying disease.

It should be noted that in 10 studies, 203 patients underwent surgical removal of ADA, followed by systemic intravenous adjuvant chemotherapy with 5-fluorouracil and oral chemotherapy with capecitabine in mono mode, or in combination with platinum-containing drugs. It is this study that we have taken as a prototype (p. 2686).

As noted by the authors in this work, an analysis of the results of such treatment showed low efficiency and high toxic effects on the patient’s body.

The technical result of the present invention is to reduce the overall toxic effect of chemotherapy on the patient's body due to their intra-arterial administration and optimization of the treatment process.

This result is achieved by the fact that in the known method of treating operable ADC, including surgical removal of the tumor and chemotherapy using 5-fluorouracil and capecitabine, according to the invention, neoadjuvant chemotherapy is carried out no later than two days before surgical removal by intraarterial bolus administration of 50 mg / m ² Abraxane slurry was not more than 3 ml of lipiodol through a catheter inserted into the gastroduodenal artery catheter is then repositioned in the celiac trunk and 5 ft ruratsil administered in an amount of 1000 mg / m ² for one hour and an additional 50 mg / m ² of oxaliplatin for 30 minutes, after which capecitabine performed adjuvant chemotherapy within 4 weeks after the surgical removal of the tumor daily orally at 2500 mg / m ² per day in 2 doses in the morning and evening for no more than 14 days, by taking capecitabine once a month for 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.

We were prompted by the results of our previously developed method for the treatment of malignant tumors of the stomach and duodenum (patent RU 2436605 C1) with intraarterial use of chemical preparations: mitomycin-C, taxotere, 5-fluorouracil, gemzar, eloxatin in combination with the oil-based radiopaque lipodiodiol providing an overall low toxicity due to intra-arterial administration of chemotherapy drugs.

This method, in our opinion, has proven itself in patients with inoperable ADA, and therefore we tried a combination of surgical removal of ADA with neoadjuvant regional oil chemoembolization, polychemotherapy, and adjuvant oral chemotherapy.

Our use of regional intra-arterial (IV) chemotherapy, in which, as is known, about 50% of the chemotherapy drug remains in the tumor node, provides a significant reduction in the overall toxic effect on the patient's body due to the delivery of the chemotherapy drug to the tumor directly through its supply vessel, which improves the quality patients' lives. Moreover, due to the "first passage" of the drug and a significant increase in its concentration around the neoplasm, the greatest antitumor effect is achieved.

Using in the treatment regimen additionally regional administration of abraxan, as an effective chemotherapy of the latest generation, allowed us to reduce its dose by more than 2 times from the generally accepted dose (recommended dose 125 mg / m ² ), thereby providing an antitumor effect in a sparing mode.

Having been engaged in the chemoembolization of tumors of parenchymal organs for several years, we introduced abraxan in suspension with lipiodol, which is able to penetrate and stay for a long time in the tumor tissue and, in suspension with abraxan, has an antitumor effect due to the provision of embolization of ADC vessels.

Abraxan 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. During 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.

Abraxan is a common, unmodified paclitaxel in the form of nanoparticles obtained by special processing of a mixture of paclitaxel with human albumin. When the drug is diluted with water, a suspension is obtained that is suitable for intravenous administration. The good solubility of abraxan in water can reduce the duration of infusion to 30 minutes instead of 3 hours when treated with taxol. The mechanism of action of abraxan is similar to the action in the form of taxol.

The use of 5-fluorouracil is known for the treatment of ADK, but our regional introduction of it into the celiac trunk makes it possible to introduce it in a lower dose.

The additional use of oxaliplatin in the treatment regimen in an amount of 50 mg / m ² , which corresponds to a dose reduction of 40% of the system dosage, provides a reduction in the overall toxic effect, while increasing the antitumor effect.

Surgical removal of the tumor no earlier than two days after the end of neoadjuvant regional chemotherapy provides optimal conditions for the operation, making it possible to reduce post-ebolization complications, eliminating adhesions and fibrotic tissue changes in the area of surgical intervention.

And the further implementation of adjuvant chemotherapy by oral administration of capecitabine in an amount of 2500 mg / m ² in 2 doses in the morning and evening for no more than 14 days 1 time per month for 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 criteria RECIST consolidates the achieved positive effect, providing an even greater enhancement of the chemotherapeutic treatment we are performing.

It should be noted that the claimed regimes and sequences of the entire treatment regimen were found by us empirically.

The essence of the method is illustrated by examples.

EXAMPLE 1. Patient P., 62 years old. Was admitted to the clinic FSBI RSCRHT Ministry of Health of the Russian Federation on January 14, 2018 with a diagnosis of duodenal adenocarcinoma cT4N0M0.

From the anamnesis: Considers herself a patient since 2008, when she first noted the appearance of obstructive jaundice. During emergency hospitalization revealed adenoma of the large duodenal nipple (BDS) with subsequent endoscopic removal. In 2010, the patient experienced a relapse of obstructive jaundice with a cholangitis clinic. Operation from 07/23/2010 - laparotomy, duodenotomy, removal of recurrent adenoma of the BDS, drainage of the common bile duct according to Keru. In 2016, a relapse of obstructive jaundice and cholangitis recurred. Performed endoscopic balloon dilatation and plastic bile duct.

On January 15, 2018, the patient was admitted to the clinic of the Federal State Budget Scientific Center of the Russian Center for Science and Technology with a diagnosis of recurrence of obstructive jaundice. Height - 164 cm, weight 64 kg, body surface area - 1.7 m ² . According to ultrasound (ultrasound) - a tumor in the area of the duodenum. According to Endo ultrasound, a creeping tumor of the BDS, choledoch, up to 18 mm in size. The histological conclusion is Adenocarcinoma.

On January 16, 2018, diagnostic angiography was performed, according to which the vascular anatomy of the hepatopancreatobiliary zone is typical. In the projection of the duodenum and pancreatic head, a formation containing tumor vessels up to 3 cm was visualized. The blood vessels of the ADC were chemoembolized by bolus injection of a 85 mg (50 mg / m ² ) abraxan emulsified in 2 ml of lipiodol through a catheter inserted into the gastroduodenal artery the catheter was reinstalled in the celiac trunk and 1700 mg (1000 mg / m ² ) of 5-fluorouracil for 60 min and 85 mg (50 mg / m ² ) of oxaliplatin were infused over 30 minutes.

01/19/2018 - Clinical blood test: Hemoglobin 125 g / L, Red blood cells 4.42 × 10 ¹² / L, Platelets 308 × 10 ⁹ / L, White blood cells 8 × 10 ⁹ / L, Neutrophils 61.9%, Lymphocytes 21.3 %, Monocytes 7.1%, Eosinophils 1.6%, Basophils 0.3%.

01/19/2018 - Biochemical analysis of blood: glucose 5.2 mmol / l, total protein 71 g / l, total bilirubin 19.0 μmol / l, ALT 36 units / liter, ACT 42 units / liter, amylase 22 units / l

The patient underwent the procedure of angiography and regional chemotherapy satisfactorily, the immediate adverse effects of regional chemotherapy were not recorded.

01/20/2018, the operation was performed. Laparotomy Split splice. Pyloric preserving pancreatoduodenal resection. Lymphatic dissection. Abdominal drainage. Elimination and plastic surgery of a postoperative ventral hernia.

Histological examination of January 26, 2018 - Highly differentiated duodenal adenocarcinoma with invasion of the pancreatic head. Lymph nodes - no tumor. Chronic cholecystitis, catarrhal exacerbation.

01/29/2018 - Clinical blood test: Hemoglobin 104 g / l, Red blood cells 3.64 × 10 ¹² / L, platelets 454 × 10 ⁹ / L, White blood cells 9.23 × 10 ⁹ / L, Neutrophils 61.9%, Lymphocytes 31 %, Monocytes 7.8%, Eosinophils 3.1%, Basophils 0.4%.

01/29/2018 - Biochemical analysis of blood: glucose 7.8 mmol / l, total protein 77 g / l, total bilirubin 8.3.0 μmol / l, ALT 36 units / liter, ACT 42 units / liter, amylase 22 units / l

02/05/2018 the patient was discharged in satisfactory condition under the supervision of the district oncologist at the place of residence with the recommendation of taking capecitabine from 02/11/2018 to 02.24.2018 (14 days) daily at 4250 mg (2500 mg / m ² ) per day in 2 doses (2250 mg in the morning and 2000 mg in the evening). The patient underwent treatment without features.

03/11/2018 to 03/24/2018 re-administration of capecitabine in the same modes. The patient's condition remained satisfactory.

Due to the good tolerance of oral chemotherapy from 04/08/2018 to 04/21/2018 and 05/06/2018 to 05/19/2018, capecitabine in the same doses was again repeated. The patient's condition remained satisfactory. No complaints. Continued to be observed at the oncologist at the place of residence.

Currently, the patient is alive and is in remission for 18 months.

To date, the proposed method has treated 5 patients with stage I-II of the disease, all are currently alive and are in remission from 5 to 18 months.

The proposed method for the treatment of operable ADA, which was developed and tested by us under clinical conditions, allowed us, due to a significant reduction in the doses of the chemotherapeutic drugs used, to achieve a decrease in the overall toxic effect on the patient’s body, ensuring a satisfactory quality of life. As a result of the satisfactory tolerance of our proposed method, it becomes possible to carry out the claimed treatment regimen in debilitated patients.

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 duodenal adenocarcinoma, including surgical removal of the tumor and chemotherapy using 5-fluorouracil and capecitabine, characterized in that neoadjuvant chemotherapy is carried out no later than two days before the surgical removal by intra-arterial bolus injection of 50 mg / m ² suspension of abraxan it is not more than 3 ml of lipiodol through a catheter installed in the gastroduodenal artery, then the catheter is reinstalled in the celiac trunk and 5-fluorouracil BB DYT in an amount of 1000 mg / m ² for one hour and an additional 50 mg / m ² of oxaliplatin for 30 minutes, after which no later than 4 weeks after the surgical removal of the tumor is performed adjuvant chemotherapy capecitabine daily orally at 2500 mg / m ² per day 2 doses in the morning and in the evening no more than 14 days, carrying out such a dose of capecitabine 1 time per month for no more than 4 months.