RU2241459C2 - Method for treatment of colorectal cancer metastasis in liver - Google Patents

Abstract

FIELD: medicine, oncology.

SUBSTANCE: method involves administration to patient of 5-fluorouracil in hepatic artery or its branches in the dose 2 g per 24 h for 3 days followed by embolization of their with suspension of recombinant interleukin-2 and lipiodol in the dose 10 ml. Roncoleukin in the dose 2 000 000 IU is used as an interleukin-2. These preparations are administrated through angiographic catheter installed by trans-femoral access. These preparations are administrated in 5-6 months after large intestine resection in the patient followed by control examination every month and the following course of above mentioned preparations is carried out and after 1-2 courses of administrations of above mentioned preparations the resection of hepatic metastasis is carried out. Method allows lasting remission, average life and life quality of patients due to cytoreductive resection of hepatic metastasis and to reduce amount and quality of intra- and post-operative complications as compared with the known method in treatment of metastasis of colorectal cancer in liver. Invention can be used in treatment of large intestine cancer with metastasis in the liver.

EFFECT: improved treatment method.

4 cl, 1 tbl 1 ex

Description

The invention relates to medicine, more specifically to oncology, and may find application in the treatment of colon cancer with liver metastases.

The development of new methods for the treatment of advanced colon cancer and the introduction into clinical practice of effective antitumor agents is an urgent problem in modern medicine. This is due to the steady increase in the number of patients with colon cancer. In Russia, 40,000 cases of colon cancer are registered annually, in the United States - 140,000. From 20 to 50% of patients with colon cancer at the initial treatment already have liver metastases. Synchronous or metachronous metastases in the liver are found in 50% of patients undergoing surgery for colon cancer. In 50% of them, liver metastases are the immediate cause of death. Five-year survival after surgical removal of metastases of colorectal cancer in the liver is 25-40%, the average life expectancy is 5-15 months.

Systemic immunotherapy and chemotherapy for colon cancer complicated by metastatic liver damage is ineffective. In addition, systemic chemotherapy is accompanied by general toxicity, which affects the quality of life of patients (Komov D.V., Barkanov A.I., Roshchin E.M. Conservative treatment of malignant tumors of the liver. // Questions of Oncologists, 1989, No. 3, p. 347-352; Roshchektayev N.V. Infusion chemotherapy of primary liver cancer. // Diagnosis and treatment of tumors of the digestive tract. Alma-Ata, 1986, p. 73-175).

A promising direction for improving the treatment outcomes of patients with advanced colon cancer is the combination of surgical treatment methods with regional intra-arterial chemotherapy and immunochemotherapy (LICHE).

A known method for the treatment of metastases of colorectal cancer in the liver (NJ Ligidakis, MD Stringarsis, K. Kokinis, K. Lyberopoulos, S. Raptis. Locoregional chemotherapy versus locoregional combined immuno-chemotherapy for patients with advanced metastatic liver disease of colorectal origin: a prospective randomized study "Hepato-Gastroenterology No. 7, V.43, 1996, p. 212-220.) The method consists in the fact that a patient with colon cancer metastases after radical removal of the primary tumor into his own hepatic (through the gastro-duodenal artery) and splenic artery administered through catheters installed during surgery, chemo and immunotherapy. The first step is regional immunotherapy: interleukin-2 and 0.5 ml of imukin (gamma-interferon) in a dose of 100 mg are mixed with 1.5 ml of super-liquid lipiodol and 0.5 ml of 58% urographin and injected into the spleen for 5 days artery and over the next 5 days into the hepatic artery.Interleukin-2 use 1 ml of Proleukin at a dose of 18 × 10 ⁶ IU. 15 days after the introduction of immunopreparations into the hepatic artery, a bolus injection of a suspension of chemo- and immunopreparations, including 0.2 mg / kg of mitomycin C, 10 mg / kg of 5-fluorouracil, 1.5 mg / kg of leucovorin, 0.5 is carried out in a bolus. ml of imukin in a dose of 100 mcg, 10 ml of super-liquid lipiodol and 2 ml of 58% urographin. The course was repeated after 2 months. The average life expectancy of patients was 16.6 months (3.75 to 32.6 months). This method is taken by us as a prototype.

The positive aspects of the chosen method are that the treatment is carried out after radical resection of the colon tumor, the drugs are selectively injected into the vessels feeding the metastatic tumors, the treatment is combined, that is, the authors combine chemo and immunotherapy. The disadvantages of the method include the fact that the drugs are injected through catheters installed in the splenic and gastro-duodenal arteries during an open operation, that is, causing a patient a surgical injury; prolonged standing of catheters in vessels (more than 2 months); during treatment, 2.1% of the patient experienced bleeding from the splenic artery in the early stages after the intraoperative installation of the catheter; catheter thrombosis occurred in 6.3% of patients; the use of Proleukin as interleukin-2 in 100% of patients in the post-embolization period caused high fever up to 38-39 ° C, chills and 45.5% of patients with myalgia; 100% of patients had metastatic tumors in the liver after treatment and did not undergo surgical resection.

Having been professionally treating widespread colon cancer complicated by metastatic liver damage for several years, we performed regional chemotherapy of the hepatic artery by introducing 6 g of 5-fluorouracil into our own hepatic artery for 3 days, followed by embolization with a suspension of doxirubicin in a dose of 60 mg and superfluid lipiodol in a volume of 10 ml. The courses were repeated a month after the preliminary examination. After 2-3 courses, liver metastases were resected.

As a result of the treatment, we did not note the positive effect of the regional treatment. All patients showed progression of the metastatic process in the liver, and after surgical resection of metastases, new metastatic lesions appeared in the lungs, and the life expectancy did not exceed 25 months. In addition, we observed side effects of regional chemotherapy, manifested by alopecia, nausea, vomiting, increased serum transaminases.

The technical result of this invention is to prolong remission, average life expectancy and improve the quality of life of patients with colon cancer metastases in the liver due to exposure to metastatic foci with a combination of locoregional immunochemotherapy and cytoreductive resection of liver metastases.

According to the invention, this result is achieved in that in a method for treating colorectal cancer metastases in the liver, the patient is injected with 5-fluorouracil 2 g per day in the hepatic artery or its branches, followed by embolization with a suspension of recombinant interleukin-2, in which Roncoleukin is taken in a dose of 2 million IU, and superfluid lipidol at a dose of 10 ml, while the above drugs are administered through an angiographic catheter installed by the femoral access.

In accordance with claim 2 of the formula, said preparations are administered by the Seldinger method.

In accordance with claim 3 of the formula, said preparations are administered approximately 5-6 months after resection of the patient’s colon.

In accordance with paragraph 4 of the formula after a preliminary examination after about 1 month, the course of administration of the above drugs is repeated.

In accordance with paragraph 5 of the formula, after 1-2 courses of administration of the mentioned drugs, a resection of liver metastases is performed.

Conducting regional intra-arterial immunochemotherapy using Roncoleukin at a dose of 2 million ME and 5-fluorouracil at a dose of 6 g, using X-ray minimally invasive and low-traumatic techniques, improved the quality of life of patients, increased the duration of their average life and disease-free period, as the quantity and quality were reduced intraoperative and postoperative complications.

The essence of the method is as follows.

A patient with colorectal cancer metastases in the liver, when admitted to the clinic, is subjected to a general clinical examination, including ultrasound, computed tomography, x-ray, histological examination, as a result of which the localization, quantity and histological structure of metastatic lesions in the liver are established. Next, a diagnostic angiography of the arterial bed of the liver is performed and an angiographic catheter is inserted with femoral access to its own hepatic artery or the right or left branches of its own hepatic artery. Within 3 days, the patient in the ward is infused with 5-fluorouracil at a dose of 2 g per day into the hepatic artery through an installed catheter. On day 4, the patient in an angiographic operating room through an installed catheter is immunoembolized by the hepatic artery with a suspension of Roncoleukin in a dose of 2 million ME and lipiodol in a volume of 10 ml. In the future, the patient undergoes a control examination every month and perform the next course of regional immunochemotherapy. After completing 1-2 courses, the patient undergoes surgical resection of liver metastases. 2 months after surgery, regional immunochemotherapy is continued.

An angiographic catheter is installed by means of thigh access to its own hepatic artery or the right or left branches of its own hepatic artery according to the Seldinger method: Seldinger S. J. Catheter replacement of the needle in percutaneous arteriography; new technique. Acta radiol., 1953.

The method is illustrated in tables.

Table 1 shows the change in the level of indicators of the cellular immunity to LIHE on days 5, 30 after 1 course of LIHE and 5 days after the second course of LIHE.

Table 2 shows the change in the humoral immunity to LIHE, on the 5th, 30th day after the 1st course of LIHE and 5th day after the 2nd course of LIHE.

An example implementation of the method.

1. Patient T., born 61 Was admitted to the clinic for the first time in April 2001. From the anamnesis it is known that in September 2000 a resection of the sigmoid colon was performed for a moderately differentiated adenocarcinoma, multiple liver metastases were found intraoperatively, not exceeding 1 cm in diameter. An examination in the clinic revealed the following changes.

A) CT: foci in S3 - 35 × 37 mm, S7 - 29 × 23 mm, S4.5 - up to 10 mm (isoechogenic);

B) OAK: normal (WBC 4.0, lymphocytes 21, ESR 22;

C) LHC: glucose - 3.6 mmol / L, total protein 89.06, ALT 55.6 IU / L, ACT 35 IU / L, amylase 301.1 IU / L;

D) Angiography: Mts in S3,7,4,5 - the dimensions are the same.

Chemoimmunotherapy (05/05/2001): HIPA 5-FU 2 g / day + for 3 days.

Roncoleukin 2 million ME and iodolipol 10.0.

Complications: hyperthermia up to 38.7 ° C for 3 days after treatment (infusion and transfusion treatment (2 l / day), - the condition returned to normal.

Examination 7 days after treatment:

Ultrasound - no change;

OAK - P-I 8, lymphocytes 10.5, ESR 54;

LHC - glucose 3.1 mmol / L, protein 71.63, ALT 15.3, ACT 42.8;

2 course (1 month after 1 course).

Screening before treatment

A) CT-C3 - 30 mm, C3 calcinate 14 mm, C5 - 10 mm, in C7 - calcinate up to 10 mm;

B) OAK - the norm;

C) LHC (normal) - glucose 3.6 mmol / L, Alt 15.6, AcT 20.9;

D) Angiography - the focus in C7 is 9 mm in diameter and C3 is 15 mm in diameter.

Chemoimmunotherapy (06/05/2001).

Complications: hyperthermia up to 38.2 ° С for 4 days.

Examination (3 days after treatment).

LHC - glucose 8.8 mmol / L, Alt 158.5, AcT 264.8, LDH 603.

D) Angiography - an accumulation of iodolipol in the metastatic foci C3 and C7 is noted on the panoramic radiograph.

3 course of immunochemotherapy (1 month after 2 courses)

Examination before RETA) CT-C3 - 14 mm, C3 - 9 mm, C4.5 - 1-2 mm, in C7 - connective tissue cords;

B) OAK - the norm;

C) LHC (normal) - glucose 5.17 mmol / L, Alt 51, AcT 46, amylase 267 Immunochemotherapy (07/15/2001):

Complications: hyperthermia up to 38.2 ° С for 3 days.

Examination (5 days after RT).

LHC - glucose 8.8 mmol / L, Alt 158.5, AcT 264.8, LDH 603.

08/14/2001 Left-sided hemihepatectomy, C4a resection, 7 - the postoperative period is smooth.

4 course immunochemotherapy (1.5 months after surgery) (immunochemotherapy)

Screening before treatment

A) CT - no metastases.

B) OAK is the norm.

C) LHC (normal) - glucose 5.17 mmol / L, Alt 51, AcT 46, amylase 267.

D) Angiography - no metastases.

Immunochemotherapy (11/05/2001).

Complications: hyperthermia up to 38.2 ° С for 3 days.

Examination (5 days after RT).

LHC - glucose mmol / L, Alt 158.5, AcT 264.8, LDH 603.

Examination after 1 month. The condition is satisfactory, no complaints, no alopecia, normal appetite, normal working capacity, with ultrasound metastases in the liver and other organs of the abdominal cavity.

To date, the proposed method has treated 8 patients. All had multiple metastatic lesions of the right and left lobes of the liver. As a result of the treatment, 1 patient showed complete regression of metastases, 7 - stabilization of the process. All patients are currently alive, fully live and work.

The treatment method in comparison with analogues has the following advantages:

1. An increase in the life expectancy of patients is already more than 2.5 years, while in known analogues this period does not exceed 27 months.

2. Improving the quality of life of patients.

Claims (4)

1. A method of treating colorectal cancer metastases in the liver, which consists in injecting 5 g of fluorouracil in the liver artery or its branches 2 g per day for 3 days, followed by embolization with a suspension of recombinant interleukin-2, which is taken Roncoleukin at a dose of 2 million ME, and lipiodol at a dose of 10 ml, while the above drugs are administered through an angiographic catheter installed with an emergency access. 2. The method according to claim 1, characterized in that the said preparations are administered 5-6 months after resection of the colon of the patient. 3. The method according to claims 1 and 2, characterized in that they carry out a control examination every month and perform the next course of administration of the above drugs. 4. The method according to claim 2 or 3, characterized in that after 1-2 courses of administration of the above drugs, liver metastases are resected.