RU2706786C1 - Method of treating inoperable pancreatic adenocarcinoma with liver metastases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine and oncology, particularly to a method of treating inoperable pancreatic adenocarcinoma with liver metastases. Method involves intra-arterial infusion introduction of 50 mg/m² oxaliplatin through a catheter into a common hepatic artery for 20 minutes, then bolus suspension 50 mg/m² abraxane in at least 5 ml of lipidol, after which the catheter is reinserted into the celiac and intra-arterially infusion 1,000 mg/m² gemcitabine for one hour with subsequent systemic chemotherapy by oral administration of capecitabine daily at 2,500 mg/m² per day in 2 divided doses in the morning and in the evening for no more than 14 days, and such treatment is carried out not more often than 1 time a month before occurrence of undesirable phenomena of II-III degree or progression of tumor process by criteria RECIST.

EFFECT: invention provides a positive therapeutic effect with a satisfactory state of patients, allowing to continue such treatment more than once.

1 cl, 1 ex

Description

The invention relates to medicine, more specifically to oncology, and may find application in the treatment of inoperable pancreatic adenocarcinoma (AP).

Adenocarcinoma is one of the types of pancreatic cancer (PCa) and the most aggressive malignant neoplasm with a negative statistical prognosis for both sexes around the world.

According to statistics from the World Health Organization, in 2018, more than 430,000 cases of prostate cancer were reported worldwide. It occupies 12th place in the structure of mortality from cancer in men and 11th place in women. According to the forecasts of the American Cancer Society, mortality from prostate cancer worldwide is 4.4%, and by 2020 it is projected to take 2nd place in mortality from cancer [AmericanCancerSociety.Facts & Figures 2018].

In the Russian Federation in 2017, 16,188 new cases of prostate cancer were recorded, of which only 17.7% had an operable stage of the disease (Art. I-II). In the structure of oncological morbidity in the Russian Federation, prostate cancer is 3.1%. It has the highest mortality rate among all malignant tumors and is the fourth most common cause of death from malignant tumors in the adult population.

According to global statistical studies, prostate cancer is more often observed in people older than 40 years, the peak incidence comes from 45-80 years. Late diagnosis of prostate cancer is due to the absence of specific symptoms in the early stages and proceeds under the guise of other diseases of the upper gastrointestinal tract.

Malignant tumors of the gastropancreatoduodenal region, which include prostate cancer, are characterized by early lymphogenous metastasis and damage to regional lymph nodes is an unfavorable factor. At the time of diagnosis, more than 70% of patients have an inoperable or locally advanced stage of the disease.

The present invention relates to the solution of an extremely important problem - the treatment of AP, which, as you know, is often characterized by the presence of liver metastases in patients, local prevalence, as well as a contraindication for performing surgical intervention on the somatic state of patients, which makes APA inoperable in such patients.

Nevertheless, it is known that to date, the most significant results in the treatment of ARV can be achieved only with radical surgical interventions. However, surgical treatment is possible only in 20% of patients with pancreatic tumor, of which only a few subsequently receive adequate adjuvant chemotherapy (AXT) [Cancer 1996; 78 (3): 664-673].

An unfavorable prognosis of the disease is associated with aggressive and not fully studied tumor biology. At the time of initial diagnosis, up to 85% of patients have liver metastases or signs of local tumor spread that do not allow for surgical treatment. Antitumor treatment in this category of patients consists only in the use of drug therapy. In accordance with international and Russian recommendations for the treatment of malignant tumors, polychemotherapy according to the FOLFIRINOX and Gem-Nab-Pac regimens is recognized as the most effective. In this case, the median overall survival remains within 6-7 months. However, the proposed systemic chemotherapy regimens are characterized by high toxicity rates. Their practical use in debilitated patients with significant weight loss, diabetes mellitus, malabsorption syndrome and often having a history of signs of obstructive jaundice with various methods of resolving it (external cholangi drainage, application of biliodigestive anastomoses) and concomitant cholangitis are associated with a large number of adverse events and serious side effects.

In recent years, targeted drugs have been actively used for various tumor diseases. EGFR and VEGF inhibitors have been shown to be highly effective in metastatic colorectal cancer and metastatic kidney cancer. High expectations from the use of targeted drugs in the treatment of pancreatic cancer did not materialize. So, Erlotinib remains the only targeted drug that has shown minimal effectiveness in patients with metastatic and locally advanced pancreatic cancer. According to the results of the study, a statistically significant increase in median survival was achieved, which was 6.24 months and 5.91 months in the Erlotinib + Gemcitabine and Gemcitabine groups, respectively, while the frequency of objective responses was not statistically different, while the frequency of adverse events was significantly higher in the group of patients undergoing treatment with a combined regimen.

In separate studies (1996–1998), drugs of the taxane group were used in the presence of AP. And yet, standard forms of drugs of this group are not widely used in the treatment of ARA due to high toxicity rates.

The desire to achieve greater effectiveness of the treatment of AP with minimal invasiveness of exposure has led to the emergence of intra-arterial administration of chemotherapy drugs with occlusion of the vessels of the tumor using effective safe radiopaque drugs.

Selective intra-arterial use of drugs is one of the ways to increase the effectiveness of antitumor treatment.

Most modern chemotherapeutic agents are not intended for intra-arterial (IV) use. To date, 5-fluorouracil remains the only cytostatic approved for iv use.

An analysis of domestic and foreign literature on X-ray endovascular studies in the treatment of tumors for the purpose of diagnosis and treatment showed great interest in the lipotropic radiopaque drug Lipiodol UltraFluid (Lipiodol) developed by Guerbet (France).

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.

In recent years, paclitaxel has been widely used to treat neoplasms. 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 intra-arterial (v / a) administration.

To overcome these negative aspects, in 2014, a new form of paclitaxel stabilized by albumin was developed, called Abraksan.

Abraxan is a conventional, 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 when treated with taxol. The mechanism of action of abraxan is similar to the action in the form of taxol.

The distinctive properties of the new drug, especially its ability to quickly penetrate through the walls of the capillaries and adsorb into the tissues, and it is tropic to the tissues of the pancreas and liver, make abraxan promising for selective intra-arterial use in prostate cancer with liver metastases.

Along with abraxan, gemcitabine is used to treat neoplasms. Gemcitabine monotherapy has long been a standard in the treatment of pancreatic cancer patients. With the development of oncology, multicomponent chemotherapy regimens have been actively used, in which gemcitabine is also successfully used. In the treatment of inoperable pancreatic cancer, the best effect was achieved with the use of FOLFIRINOX and gemcitabine + abraxan regimens.

This method, in our opinion, is the closest to the proposed one and was taken as a prototype (Application for patent dated 05/20/2011 No. 2012156275/15, USA DISAI Neil P., COOH-SHIONG Patrick).

The authors note that in patients with pancreatic cancer, it is possible to use gemcitabine in combination with abraxan, including intra-arterial, but without a detailed description of the procedure. The dose of abraxan, depending on the nosology, is from 100 to 400 mg / m ² . It is also noted that such administration can be carried out depending on nosology in various ways, for example, intravenously, intraarterially, intraperitoneally, intra pulmonary, oral, inhalation, intravesicular, intramuscularly, intratracheally, subcutaneously and even intraocular, intratracheal, transmucosal and transdermal.

It should be noted at the same time that the authors did not give specific examples of the use of such a composition, the treatment of each of the given nosologies with its use, and the optimal tactics of management of specific patients, including those with AR with metastases to the liver, which would require specific analysis and systematization of the obtained data.

The technical result of the present invention is to optimize the treatment of AP with liver metastases due to the use of oxaliplatin and capecitabine along with abraxan and gemcitabine in the treatment regimen, as well as the route and sequence of their administration.

This result is achieved by the fact that in the known method for the treatment of inoperable APA with metastases in the liver, including intra-arterial administration of the chemotherapy drugs abraksan and gemcitabine, according to the invention, oxaliplatin is additionally used as chemotherapeutic agents, which are injected into the common hepatic artery in an amount of 50 mg / m ² in for 20 minutes, then a suspension of Abraxane at 50 mg / m ² is not more than 5 ml of lipiodol carried selective embolization of hepatic artery, whereupon the catheter is repositioned into h evny barrel and gemcitabine in an amount of 1000 mg / m ² administered intraarterially infusion for one hour, after which operate chemotherapy through oral capecitabine daily 2500 mg / m ² per day in 2 divided doses, morning and evening not more than 14 days, and a chemotherapy carry out no more than 1 time per month until the appearance of adverse events of the II-III degree or the progression of the tumor process according to the RECIST criteria.

Previously, we developed a method for the treatment of pancreatic malignant tumors (RF patent No. 2156137), which served as the basis for further improvement of methods for treating pancreatic tumors, including its adenocarcinoma.

The method includes regional chemotherapy, while the chemotherapeutic drug is administered in radiopaque oil in an amount of 1 / 5-1 / 3 of its single dose into the arteries supplying the tumor zone with blood, previously reducing blood flow in them distal to the place of its administration, moreover, such chemotherapy is carried out repeatedly with an interval not less than 1 month. In the patent, doxorubicin 10 mg / m ² or gemzar 200 mg / m ^{2 is} used as a chemotherapeutic drug, and lipiodol in an amount of 3-10 ml per administration is used as a radiopaque oil.

The method allows to reduce the general toxic effect of chemotherapeutic agents, including highly toxic doxorubicin, by depositing them directly in the pancreas and reducing their dose. The patent noted that the result of using such a minimally invasive method of treatment in inoperable patients is comparable in life expectancy with radically operated patients. This method served as the basis for our development of other low-toxic methods of treating pancreatic malignant tumors, including the development of a method for the treatment of inoperable pancreatic adenocarcinoma with liver metastases, which we offer as the present invention.

The use of oxaliplatin with gemcitabine is known in combination with surgery as a neoadjuvant regional chemotherapy, while gemcitabine is administered in a suspension of lipiodol in the gastroduodenal artery, supplemented with an infusion of oxaliplatin with subsequent adjuvant chemotherapy, by intraarterial infusion of hepticulin and hepticulin No. 2, p. 54-59).

The use of oxaliplatin is also known in the treatment of pancreatic cancer without surgery, including in combination with gemcitabine. Their synergistic effect in the culture of tumor cells was studied, and in patients with ARV who received a combination of these drugs, in comparison with gemcitabine monotherapy, they managed to get a greater response. At the same time, despite higher treatment efficacy indicators, a higher toxicity of such a combination was noted in the literature compared with gemcitabine monotherapy, in particular, the prevalence of adverse events such as vomiting, thrombocytopenia, and neuropathy was reported. Nevertheless, such a combination was recommended for chemotherapeutic treatment of AP (Moiseenko V.E. Rationale for the use of perioperative regional chemotherapy with gemcitabine and oxaliplatin in the combined treatment of ductal adenocarcinoma of the pancreatic head, abstract of dissertation for Candidate of Medical Sciences, Federal State Budgetary Institution Scientific Medical Center. Ac. AM Granova ”, S.-Pb, 2018).

We tried to introduce oxaliplatin into our chemotherapeutic treatment regimen for inoperable liver adenocarcinoma with metastases in the liver as one of the steps of our method, introducing it into the common hepatic artery to affect liver metastases, while additionally performing selective embolization of the liver artery with a suspension of abraxan in lipiodole for greater enhancement of the effect of chemotherapy on metastases, and subsequent reinstallation of the catheter into the celiac trunk and the infusion of gemcite ins through the same catheter as we have shown in the treatment of inoperable patients, contributes to an even greater antitumor effect, enhancing the chemotherapeutic effect on both the metastases in the liver, and the pancreas tumor. And further chemotherapy by oral administration of capecitabine in an amount of 2500 mg / m ² 2 times a day in the morning and evening no more than 14 days a month no more than 1 time per month until the appearance of adverse events of the II-III degree or the progression of the tumor process according to the RECIST criteria consolidates the achieved a positive effect, providing an even greater increase in the chemotherapeutic effect on the pancreatic tumor and liver metastases.

It should be noted that all doses of chemotherapy drugs, the sequence and temporary modes of their administration were determined by us empirically in the process of treating patients.

The essence of the method is illustrated by example.

EXAMPLE 1. Patient E., 63 years old. He was admitted to the clinic of the Federal State Budget Scientific Research Center for Science and Technology of the Ministry of Health of the Russian Federation on April 22, 2019 with a diagnosis of Adenocarcinoma of the pancreas body cT ₃ N ₁ M ₁ (hepar) IV st.

From the anamnesis: considers himself sick since November 2018, when the pain in the epigastric region first appeared, in connection with which he sought medical help at the place of residence. According to ultrasound of the abdominal cavity from 11/13/2018: diffuse changes in the liver. I did not receive treatment. At the end of January 2019, due to increased pain, he again sought medical help. According to the ultrasound of the abdominal organs from 01/16/2019: without pathological changes in the abdominal organs. Marked changes according to clinical, biochemical blood tests were not detected. Continued self-treatment.

In March 2019, according to the next ultrasound of the abdominal cavity from 03/27/2019: the formation of the pancreas. The implementation of multispiral computed tomography (MSCT) of the abdominal organs is recommended. According to the MSCT of the abdominal organs from 04/02/2019: the formation of the pancreas body size 58 * 38 mm, with uneven, fuzzy contours. In the liver, single hypoechoic formations of a secondary nature (mts) were determined, the largest in the 7th segment, up to 28 * 26 mm in size. Enlarged parapancreatic lymph nodes up to 8 * 4 mm. Hospitalized in the Murmansk Regional Oncology Center in order to verify the diagnosis. 04.17.2019, a trepan biopsy of the formation of the pancreas was performed. According to histological examination, adenocarcinoma cell complexes. Directed for consultation in St. Petersburg in the Russian Science Center RHT.

Upon admission to the clinic of the Russian Science Center RHT on 04/22/2019, complaints of severe pain in the epigastric region with radiation to the lumbar region. Objectively: satisfactory condition, height 176 cm, weight 70 kg, body surface area (PPT) = 1.86 m ² . The skin is clean, the lymph nodes are not enlarged. Borders of the heart within normal limits, heart rate (HR) 68 / 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 intraarterial chemoembolization of the liver.

The results of the examination before the procedure: Oncomarkers from 04/17/19: CA19-9 - 3331.55 IU / ml, CEA <1.12 ng \ ml.

Clinical blood test dated 04/22/2019: Hemoglobin 141 g / l, red blood cells 5.03 × 10, ² / l, platelets 247 × 10 ⁹ / l, white blood cells 10.54 × 10 ⁹ 1 l, neutrophils 63.2%, lymphocytes 18%, Monocytes 6.7%, Eosinophils 11.4%, Basophils 0.7%.

Biochemical analysis of blood from 04/22/2019: glucose 5.67 mmol / L, total protein 79 g / L, total bilirubin 8.9 μmol / L, ALT 47 U / L, ACT 28 U / L, amylase 17 U / L.

04/22/2019, performed diagnostic angiography. Upper mesentericography. Celiacography.

Under angiooperative under local anesthesia with 20 ml of a 1% solution of novocaine, the right femoral artery was punctured according to Seldinger. For diagnostic angiography, the Hook 5 F catheter is alternately inserted in the superior mesenteric artery, celiac trunk, and common hepatic artery. On angiograms, the vascular anatomy of the hepatopancreatoduodenal zone is typical. Arteries are passable, pronounced usenation of the splenic artery with narrowing of the lumen up to 30%, from the mouth 3 cm long. Usage of the common hepatic artery from the mouth for 2 cm. Multiple formations of mixed vascularization from 1 to 4 cm in diameter are visualized in the projection of both liver lobes in a projection of 7 segments. Hypovascular body formation of the pancreas up to 6 cm in diameter. The portal and superior mesenteric veins are muftiformly narrowed (squeezed by the tumor) from the outside, the splenic vein is not visualized (invasion), the outflow along the collaterals. Hepatopetal blood flow.

Conclusion: a locally advanced pancreatic body tumor (arterial and venous invasion), metastatic liver damage.

Immediately after performing diagnostic angiography dated 04/22/2019, they started the procedure of intra-arterial chemoinfusion and intra-arterial chemoembolization of the liver.

The first stage was an intra-arterial infusion into the common hepatic artery of an aqueous solution of oxaliplatin in an amount of 94 mg (50 mg / m ² ). To prepare the solution, a glucose solution of 5% - 50 ml was used, which was mixed with oxaliplatin lyophilisate immediately before administration. The oxaliplatin solution was infused into the common hepatic artery for 20 minutes. Immediately after the end of this procedure, intra-arterial chemoembolization of the liver with a suspension consisting of 94 mg (50 mg / m ² ) of abraxan and 5 ml of lipiodol was performed. The suspension was prepared immediately before the embolization procedure. Abraxan lyophilisate was dissolved in 10 ml of physiological saline and, after complete dissolution, lipiodol was added to it, and the resulting suspension was emulsified by repeated mixing, after which it was introduced into the hepatic artery. During embolization, the patient noted severity, moderate pain in the right hypochondrium, a feeling of “warmth” in the abdominal cavity. And yet, the patient underwent this procedure without features. 30 minutes after the administration of the chemoembolizate, intraarterial chemoinfusion of an aqueous solution of 1880 mg (1000 mg / m ² ) of gemcitabine was started. Its solution was prepared immediately before administration by dissolving gemcitabine lyophilisate in 50 ml of physiological saline. Its introduction was carried out at a rate of 50 ml / h. After completion of intra-arterial chemoinfusion, the arterial catheter was removed, a pressure bandage was applied to the area of the femoral artery puncture. From the moment of removal of the arterial catheter, the patient was immobilized for 8 hours.

On April 23, 2019, the patient began oral administration of capecitabine at 4650 mg (2500 mg / m ² ) per day in 2 divided doses (2450 mg in the morning and 2200 mg in the evening).

Clinical blood test dated 04.24.2019: Hemoglobin 130 g / l, RBC 4.72 × 10 ¹² / L, platelets 208 × 10 ⁹ / L, White blood cells 12.6 × 10 ⁹ / L, Neutrophils 73.6%, Lymphocytes 10 , 8%, Monocytes 4.6%, Eosinophils 10.5%, Basophils 0.5%.

Biochemical analysis of blood from 04.24.2019: glucose 6.03 mmol / L, total protein 70 g / L, total bilirubin 16.1 μmol / L, ALT 62 U / L, ACT 56 U / L, amylase 14 U / L.

04/26/2019 g the patient was discharged from the hospital in satisfactory condition for taking capecitabine on an outpatient basis daily for 14 days (until 05/06/2019 g) with the control appearance of the patient after the end of taking capecitabine for testing.

05.06.2019 g. The patient was examined on an outpatient basis. Complaints of moderate epigastric pain. Objectively: the condition is satisfactory, the skin is clean, the lymph nodes are not enlarged, weight 72 kg, PPT = 1.88 m ² . The boundaries of the heart are within normal limits, heart rate is 68 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.

05/22/2019 the patient is re-hospitalized in the clinic to continue treatment. 05/23/2019 the second course of intraarterial chemoinfusion and intraarterial chemoembolization of the liver was performed similarly to the first stage (oxaliplatin, suspension of abraxan in lipiodol, gemcitabine). After completion of the procedure, the patient's condition is satisfactory. The treatment was transferred without features. From May 24, 2019 to June 7, 2019, oral administration of capecitabine daily again at 2500 mg per day in 2 divided doses in the morning and evening for no more than 14 days.

Clinical blood test dated 05/27/2019: Hemoglobin 125 g / l, red blood cells 4.57 × 10 ¹² / l, platelets 216 × 10 ⁹ / l, white blood cells 8.1 × 10 ⁹ / l, neutrophils 75.7%, lymphocytes 15 , 5%, Monocytes 2.2%, Eosinophils 6.1%, Basophils 0.5%.

Biochemical analysis of blood from 05/27/2019: glucose 5.69 mmol / L, total protein 70 g / L, total bilirubin 9 μmol / L, ALT 84 U / L, ACT 60 U / L, amylase 15 U / L.

05/27/2019 the patient was discharged in satisfactory condition with recommendations to continue taking capecitabine and perform computed tomography of the abdominal cavity with intravenous contrast to assess the course of the underlying disease with subsequent appearance on an outpatient basis.

06/20/2019, computed tomography of the abdominal organs with intravenous contrast was performed. Conclusion: signs of stabilization of the disease compared with computed tomography data from 04/02/2019.

The patient is recommended to continue in the clinical setting similar procedures for intra-arterial chemoinfusion, intra-arterial chemoembolization of the liver and subsequent outpatient administration of capecitabine in the same amounts.

Conclusion: a patient with inoperable pancreatic adenocarcinoma with bilobar metastatic liver damage. The standard of treatment for this group of patients is palliative systemic chemotherapy and symptomatic treatment. In most cases, a full-fledged systemic polychemotherapy is limited by the low general status of patients and high toxicity profiles of the treatment. On the other hand, conducting systemic chemotherapy in a reduced mode, as we have done, seems to be ineffective.

The gentle regional polychemotherapy we performed in combination with intra-arterial chemoembolization allowed us to achieve good tolerance indices while maintaining stabilization of the disease, according to computed tomography, in accordance with the RECIST criteria, stabilization of the CA19-9 tumor marker. 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 still remains satisfactory.

To date, the patient held 2 courses of the claimed method of treatment. Being in a satisfactory condition, the patient continues to be observed with the possibility and necessity, in our opinion and experience, of continuing treatment in the same mode.

By July 2019, the proposed method carried out the treatment of 5 patients with achieving stabilization of the underlying disease, which distinguishes our claimed method from the known ones.

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 inoperable pancreatic adenocarcinoma with metastases in the liver, including intra-arterial administration of chemotherapy drugs Abraxan and gemcitabine, characterized in that oxaliplatin is additionally used as chemotherapy, which is injected into the common hepatic artery in an amount of 50 mg / m ² for 20 minutes bolus suspension Abraxane at 50 mg / m ² is not more than 5 ml of lipiodol carried selective embolization of the hepatic artery, whereupon the catheter is repositioned in the womb the first barrel and gemcitabine in an amount of 1000 mg / m ² administered intraarterially infusion for one hour, after which operate chemotherapy through oral capecitabine 2,500 mg / m daily ² per day in 2 divided doses, morning and evening up to 14 days following chemotherapy is performed not more than 1 time per month until the appearance of adverse events of the II-III degree or the progression of the tumor process according to the RECIST criteria.