RU2755329C2 - Method for the treatment of unresectable hylus cholangiocarcinoma - Google Patents

Abstract

FIELD: medicine; oncology.

SUBSTANCE: invention relates to medicine, namely to oncology; it can be used in the treatment of unresectable hylus cholangiocarcinoma. A method includes selecting patients by Bismuth-Corlett IV or IIIa, or IIIb type with contralateral damage to vascular structures, conducting systemic chemotherapy, surgical staging and liver transplantation. Additionally, a patient is subjected to targeted intra-flow photodynamic therapy before systemic chemotherapy and, no earlier than 3 days later, transarterial chemotherapy once with cisplatin in the amount of 25 mg/m² and gemcitabine in the amount of 1000 mg/m². Systemic chemotherapy is carried out no earlier than 7 days after transarterial chemotherapy in the same regimens once, repeating it no earlier than 21 days later. The specified treatment is repeated after 18 days in the same regimens at least 3 times before surgical staging, with the continuation of treatment until liver transplantation.

EFFECT: use of the invention makes it possible to reduce the overall toxic effect on the patient’s body, to stop tumor growth by using photodynamic therapy and transarterial chemotherapy in the treatment regimen, as well as to treat hylus cholangiocarcinoma in patients who previously could not be performed with radical intervention by resection of the liver and extrahepatic bile ducts, to improve results of liver transplantation in this category of patients.

1 cl, 1 ex

Description

The invention relates to medicine, more precisely to surgery and oncology, and can be used as a treatment for tumors of the bile ducts.

Cholangiocellular carcinoma (CCC) is a rare form of cancer and accounts for 2-3% of all malignant neoplasms of the gastrointestinal tract. Hylus cholangiocarcinoma ranks second among primary malignant tumors of the liver. Currently, there has been a clear tendency towards an increase in the number of patients with proximal bile ducts, and due to the disappointing long-term results of surgical treatment, this type is one of the leading causes of mortality from primary hepatobiliary tumors.

Hilus cholangiocarcinoma (HCC) belongs to the group of tumors of the hepatobiliary system, developing from the epithelium of the bile ducts and characterized by high mortality and low efficiency of standard methods of surgical and conservative treatment. According to a number of authors, the tumor accounts for about 70% of all tumors of the biliary tree.

According to available data, the absolute number of newly diagnosed liver and intrahepatic duct cancer in 2017 was 5092 in men and 3704 in women, and 1382 in men and 2514 in women for gallbladder and extrahepatic duct cancer. The average annual growth rate of morbidity per 100 thousand population in 2017 was 5.99% for liver tumors and intrahepatic cholangiocarcinoma and 2.65% for cancer of the gallbladder and extrahepatic bile ducts [Malignant neoplasms in Russia in 2017 (morbidity and mortality), Moscow 2018, pp. 13-17].

Today, there are various treatments for HCA.

The standard of treatment for resectable HCC is surgical intervention in the volume of liver resection. However, according to a number of studies, resectability in hilus cholangiocarcinoma is about 30-50%, 5-year survival rate, provided R0 resection is performed, is no more than 30-40%, while the recurrence rate within 5 years reaches 70% [Hilar cholangiocarcinoma: diagnosis, treatment options, and manage ment. Hepatobiliary Surg Nutr. 2014 Feb; 3 (1): 18-34. Klatskin tumor: Diagnosis, preoperative evaluation and surgical considerations. Cir Esp. 2015 Nov; 93 (9): 552-60. Recurrence Rate and Pattern of Perihilar Cholangiocarcinoma after Curative Intent Resection. J Am Coll Surg. 2015 Dec; 221 (6): 1041-9].

In addition, in 50% of cases, after radical surgery, local recurrence occurs, and in 30-40% of cases, distant metastasis of the tumor. The high frequency of a positive surgical margin is due to the lack of a detailed understanding of the extent of the process due to the extended, predominantly proximal periductal tumor growth with a macroscopically unchanged bile duct wall. As for the long-term results of liver resection in portal sites, the five-year survival rate of patients with them is 5-15%.

Thus, it should be recognized that at the moment resection is considered the preferred treatment option, given the technical feasibility of its implementation, however, it is indicated and feasible only for a narrow group of patients, and although oncological results, although they are the best available, often do not allow us to speak about 5 -year survival rate of more than 30%. As a rule, the disease is diagnosed with the appearance of obstructive jaundice, acholic stools and dark urine, which is already accompanied by itching, cholangitis, the formation of cholangiogenic abscesses and weight loss.

Given these features of the course of HCC, the majority of patients at the time of treatment already have unresectable forms of Bismuth-Corlett type IV, IIIa, IIIb with contralateral lesions of vascular structures (a branch of the hepatic artery or portal vein) and corresponds to TNM T4N0M0 IIIC stage. This form of tumor spread does not allow performing radical surgery (liver resection in various volumes).

Moreover, this category of patients can be included in the developed treatment regimen if certain criteria are met. These are the patients:

1) with a diagnosis of extrahepatic cholangiocarcinoma (Klatskin's tumor) corresponding to type IV according to the Bismuth-Corlett classification type IV, IIIa, IIIb with contralateral lesions of vascular structures (a branch of the hepatic artery or portal vein) and corresponds to TNM T4N0M0 stage IIIC, and T4N0M0 stage IIIC classification TNM;

2) the localization of the tumor should be higher than the cystic duct with a diameter of no more than 5 cm;

3) there was no previous surgical intervention: resection and transperitoneal biopsy of the tumor;

4) drainage of the bile ducts is performed;

5) performed cytological and histological examination;

6) the patient's ECOG status is not more than 2;

7) a patient without acute cholangitis;

8) the level of total bilirubin is not higher than 80 μmol / l;

9) a patient without significant concomitant diseases, allowing chemotherapy and criteria for the inclusion of liver transplantation;

10) the absence of signs of a systemic inflammatory response.

Such unresectable forms of cholangiocarcinoma, both in the Russian Federation and in most countries of the world, are treated exclusively with palliative methods. To carry out radical treatment of this category of patients, a multidisciplinary approach is required, which can only be provided in specialized centers.

For a long time engaged in the professional treatment of such tumors, as well as liver transplantation, we came to the conclusion that this category of patients (unresectable forms of Bismuth-Corlett type IV and corresponds to TNM T4N0M0 stage IIIC) with a multidisciplinary approach, which implies a combination of various methods treatment, allows you to perform radical surgery (liver transplantation).

In the case of technically unresectable HCC, treatment is palliative, and its results and prognosis differ little from those in the disseminated process and, as a rule, are caused by rapidly progressing biliary obstruction. The primary task in the supervision of such patients is biliary decompression in order to relieve obstructive jaundice and purulent cholangitis. The goals of palliative care are to alleviate symptoms associated with tumor growth and improve quality of life.

Currently, the method of choice for biliary decompression for this category of patients is percutaneous-transhepatic cholangiostomy due to the impossibility of retrograde drainage in more than half of cases with strictures of the proximal extrahepatic bile ducts.

The standard antitumor treatment of unresectable HCC, as well as for any form of inoperable locally advanced or metastatic cholangiocellular cancer according to Russian and foreign clinical guidelines, is systemic chemotherapy according to the GemCis scheme (gemcitabine / cisplatin) or GemCap (sterecitabine / capecitabine therapy) with fluoropyrimidines [NCCN Guidelines 2019, RUSSCO 2017] or other options for chemotherapy and radiation therapy, depending on the somatic status of the patient, toxicity, individual intolerance, and developing complications.

Moreover, according to the combined statistics of the effectiveness of these methods of treatment of all inoperable malignant neoplasms of the biliary structures, the median overall survival is 8-10 months [VV Breder. Cancer of the biliary system. Practical oncology. 2012; 13 (4): 269-275]. Some of the best results achieved with chemoradiation therapy show a 4-year survival rate of 30% [Chemoradiation treatment with gemcitabine plus stereotactic body radiotherapy for unresectable, non-metastatic, locally advanced hilar cholangiocarcinoma Results of a five year experience.].

A relatively new progressive method of treating unresectable HCC is endobiliary photodynamic therapy (PDT), based on the photodynamic effect, first discovered by O. Raab in 1900. The technique includes intravenous administration of a photosensitizing drug that selectively accumulates in the tumor tissue and its subsequent activation by a beam of light of a certain length waves through a thin tube-emitter, which triggers a cascade of intracellular reactions leading to the death of tumor cells. The effectiveness of PDT in combination with biliary decompression is confirmed by numerous studies, in some of which the difference in life expectancy was fivefold [Successful photodynamic therapy for nonresectable cholangiocarcinoma: a random-ized prospective study. Gastroenterology. 2003; 125 (5): 1355-1363. Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am J Gastroenterol. 2005; 100 (11): 2426-30. Photodynamic therapy prolongs metal stent patency in patients with unresectable hilar cholang-iocarcinoma. World J Gastroenterol. 2012 Oct 21; 18 (39): 5589-94. Photodynamic therapy for hilar bile duct cancer: clinical evidence for improved tumoricidal tissue penetration by temoporfin. Photochem Photobiol Sci. 2013; 12: 1065-1073]. The presence of percutaneous-transhepatic drainages in the biliary tree in patients with HCC after decompression implies the relative ease of delivery of the emitter to the affected area and the possibility of multiple repetitions of the procedure. The most frequent complications such as cholangitis (cholangiogenic sepsis) (in a third of cases) and phototoxic reaction (about 10%) are helped by timely antibiotic therapy according to the sensitivity of the flora and the correct light regime, including minimal sun exposure and wearing sunglasses.

It is known that today, the only possible way to achieve radical treatment for this category of patients is liver transplantation, as a way to completely remove the tumor even if the vascular structures of the liver hilum are damaged. But this operation is not indicated for all patients with unresectable forms of HC, due to the spread of the disease at the time of contacting a medical institution. The underlying disease is already associated with the development of complications such as obstructive jaundice with the development of cholangitis and systemic inflammatory reactions.

The use of the therapeutic option in the form of liver transplantation for patients with HCC has been undertaken since 1980, and, despite the clear reasonable theoretical advantage in the possibility of complete removal of the affected organ with a tumor-free resection margin, the results left much to be desired. Clinics performing HCC transplantation reported a 3-year survival rate of about 30% [Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg 2004; 239: 265]. Based on this, the world medical community has come to the conclusion that a more radical operation due to hepatectomy of the recipient cannot significantly improve long-term results. Moreover, postoperative immunosuppression significantly increases the risk of tumor progression and often leads to rapid death of the patient. Despite the poor results, the cohort of patients with negative margins and no regional lymph node metastases had much better survival rates. In addition, a small group of patients at the Mayo Clinic who received only chemoradiotherapy without subsequent surgical treatment had a 22% 5-year survival [Int J Radiat Oncol Biol Phys 1997; 39: 929]. The unsatisfactory results of standard methods of HCA treatment were a trigger for the active development of combined methods. Based on the information obtained about the similar efficacy of chemoradiation therapy for HCC and the knowledge that the development of the disease is usually associated with local recurrence, and not with distant metastases [Patterns of initial disease recurrence after resections. Cancer 2003], a Nebraska transplant team pioneered a strategy of high-dose neoadjuvant brachytherapy in combination with 5-fluorouracil (5-FU) chemotherapy followed by liver transplantation [Liver transplantation for cholangiocarcinoma. Charles 2010 - 25]. Although there were significant complications associated with high-dose brachytherapy, early results were promising for the development of local recurrence. Subsequently, the Mayo Clinic adopted this concept, developing a similar protocol for neoadjuvant therapy followed by liver transplantation in 1993. The protocol combined the benefits of radiation therapy, chemotherapy, liver transplantation, and appropriate selection of patients with localized, inoperable HCC. Preliminary results for 11 patients reported in 2000 were encouraging [Liver transplantation for cholangiocarcinoma. 2010. 26], and an update in 2004 reported 82% 5-year survival in 28 patients. Thus, we came to the conclusion that in order to carry out such a radical method of treatment as liver transplantation in patients with unresectable forms of HCC in order to improve long-term results of treatment and increase relapse-free survival, it is necessary to carry out a complex combined treatment.

Method "Protocol for the treatment of unresectable Klatskin tumor according to the protocol of the Mayo Clinic" described by d Liver transplantation for cholangiocarcinoma // Transplant International, 2010, T. 23. - No. 7. - P. 692-697, in our opinion, is the closest to the proposed one and is taken by us as a prototype.

This method involves careful selection of patients with HCC, which is considered anatomically inoperable by an experienced hepatobiliary surgeon. Criteria for anatomical inoperability include bilateral segmental bile duct involvement, portal vein invasion, unilateral segmental bile duct involvement with contralateral vascular invasion, and atrophy of one of the liver lobes with contralateral segmental bile duct involvement or vascular invasion. The tumor invasion of the hepatic hilum vessels is not a contraindication to transplantation. According to the inclusion criteria, the tumor size should be no more than 3 cm. According to the computed tomography (CT) of the chest, CT or magnetic resonance imaging (MRI) of the abdomen, intra- or extrahepatic metastases should be excluded. The method excludes patients with intrahepatic cholangiocarcinoma or gallbladder involvement. Previous surgery, percutaneous or endoscopic ultrasound transperitoneal biopsy has been shown to increase the risk of dissemination of tumor cells in the peritoneum and are now considered absolute contraindications for transplantation. Candidates should not have received any specific anticancer treatment before undergoing neoadjuvant therapy, and they should not have active infections or diseases that would interfere with either neoadjuvant therapy or liver transplantation. All candidates for transplantation according to this method undergo abdominal revision and surgical staging. This is done when patients are at the top of the waiting list for a liver transplant from a deceased donor or the day before a living donor transplant. The revision includes a thorough examination of the abdominal cavity and assessment of the hepatic hilum area. At least one lymph node along the own hepatic artery and another along the common bile duct is excised, even if the regional nodes appear normal. The liver is palpated carefully to detect intrahepatic metastases that may have gone unnoticed in preoperative studies.

Neoadjuvant therapy is aimed at the primary tumor and regional lymph nodes, carried out in the mode of external beam radiation therapy 1.5 Gy twice a day up to a total dose of 45 Gy. Intraductal brachytherapy is performed with transcatheter irradiation with iridium 2 weeks after completion of radiation therapy. 20 Gy is delivered at a radius of 1 cm for about 20-25 hours via endoscopic or percutaneous-transhepatic bile drainage. Also, during radiation therapy, patients receive 5-FU, and then capecitabine immediately prior to transplantation.

Taking into account the effectiveness of HCA treatment according to the Mayo Clinic protocol, it should be noted that this technique is not without a number of disadvantages.

Thus, the performance of radiation and intraductal brachytherapy is often accompanied by vascular complications, which, in our opinion, is explained by the pronounced proliferation of connective tissue and the formation of coarse cicatricial structures in the hepatoduodenal ligament. This cannot but affect the intraoperative precision of dissection of anatomical structures and the formation of anastomoses, which significantly complicates the performance of vascular reconstruction during liver transplantation.

In addition, the systemic chemotherapy carried out in the prototype is quite toxic. At the same time, repeated execution of it increases the toxicity even more.

The technical result of the present invention is to reduce toxicity due to the additional use of photodynamic therapy and transarterial chemotherapy in the treatment regimen.

This result is achieved by the fact that in the known method for the treatment of unresectable hilus cholangiocarcinoma, including the selection of patients of the Bismuth-Corlett type IV or IIIa, or IIIb with contralateral lesions of the vascular structures, systemic chemotherapy, surgical staging and liver transplantation, according to the invention, in addition to the patient before conducting systemic chemotherapy is performed aiming intraductal photodynamic therapy and no earlier than 3 days transarterial chemotherapy once cisplatin preparations in an amount of 25 mg / m ^2, and gemcitabine in an amount of 1000 mg / m ^2, and systemic chemotherapy is carried out not earlier than 7 days after transarterial chemotherapy in the same modes, once, repeating it no earlier than 21 days later, and such treatment is carried out every 18 days at least 3 times before surgical staging, with the continuation of treatment until liver transplantation.

The performance of photodynamic therapy (PDT) is widely known in clinical medicine. This makes it possible to selectively accumulate a photosensitizer in the tumor tissue, followed by its activation by light using a fiber with a cylindrical diffuser, which triggers a cascade of intracellular reactions leading to the death of the tumor cell. However, the use of PDT in our proposed regimens and in combination with transarterial and systemic chemotherapy is not obvious to obtain the clinical result that we have achieved.

The implementation of transarterial chemotherapy with drugs cisplatin in the amount of 25 mg / m ² and gemcitabine in the amount of 1000 mg / m ² allows you to create a high concentration of the chemotherapy drug in a limited anatomical region, therefore, the cytostatic effect increases and the systemic toxic effect on the patient's body decreases. This is especially important for this category of patients. And its implementation no earlier than 3 days after PDT eliminates complications that may interfere with further treatment (cholangitis, cholangiogenic sepsis).

Carrying out in the same modes and with the use of chemotherapy drugs selected by us for systemic chemotherapy allows us to act directly on the tumor itself, as well as reduce the risks of distant metastasis. Carrying it out 7 days after transarterial chemotherapy and repeating it no earlier than 21 days later helps to reduce the toxic effect of chemotherapy drugs on the body and restore the hematopoietic germ.

Repetition of such treatment every 18 days and at least 3 times before surgical staging ensures the development of therapeutic pathomorphosis due to PDT, and also reduces the toxic effect on the body of systemic chemotherapy by alternating it with transarterial.

Due to the fact that the tumor is of a pronounced malignant nature, the proposed method of treatment at least 3 times and before liver transplantation allows you to suspend tumor growth and achieve a significant clinical effect in the form of reducing pain, stopping signs of obstructive jaundice and normalizing clinical and biochemical blood parameters.

All this creates favorable conditions for the subsequent performance of liver transplantation.

Our long-term experience shows that our proposed method of treatment followed by liver transplantation can significantly improve both the immediate and long-term results of HCA treatment and increase the relapse-free period and overall survival.

The essence of the method is illustrated by examples.

Example 1.

Patient B., 49 years old,

From the anamnesis: since June 2014, I began to notice icterus of the skin and mucous membranes. On an outpatient basis on 06/09/2014, he turned for a consultation at the clinic of the Federal State Budgetary Institution "RNTSRKhT im. ac. A.M. Granov ".

According to the ultrasound examination of the abdominal cavity, a focal formation was found in the area of the liver hilum. Magnetic resonance cholangiopancreatography was performed in August 2014: a neoplasm of irregular shape, 55x15 mm in size, spread along the common hepatic duct above the area of confluence with the cystic duct to the confluence area in the hepatic hilum and spread to the right and left lobe. The level of Ca19-9 tumor marker in the blood is 1500 IU / ml.

According to computed tomography data from August 2014, in the liver gates along the common hepatic duct, a mass 57 × 14 mm in size, unevenly accumulating contrast. The neoplasm is located in the area of the gate of the liver, grows and compromises the right branch of the portal vein. There were enlarged lymph nodes in the region of the celiac trunk, hepatic hilum. Thus, a preliminary diagnosis was established: Hilus cholangiocarcinoma T4N0M0. Stage IV. Bismuth-Corlett IV.

In September 2014, the patient was admitted to the clinic of the N.N. ac. A.M. Granov, where external-internal drainage of the right lobar duct, common hepatic duct, common bile duct was performed, tumor biopsy, percutaneous installation of internal stents was performed on September 10, 2014. According to the histological report, supplemented by an immunohistochemical study dated September 17, 2014 - cholangiocarcinoma ...

Discharged in satisfactory condition on September 18, 2014.

Hospitalized in the surgical department of the clinic of the Federal State Budgetary Institution "RNTSRHT named after ac. A.M. Granov "10/12/2014, It was decided to conduct a session of intraductal photodynamic therapy (PDT). In the conditions of the X-ray operating room on 13.10.2014, the removal of the right and left cholangiodrainages on controlled metal conductors was performed. Parallel to the puncture canal, the optical fiber of the PDT apparatus is installed at the level of the left and right. After preliminary intravenous administration of Radachlorin 70 mg (for 2 hours), intraductal PDT was performed on the Lakhta-Milon apparatus with a wavelength of 662 nm (with an error of 5 nm), a fiber with a cylindrical diffuser with a radiation power of 1 W. The total dose of energy is 350 J / cm ^∧ 2. Cholangio drainage Flexima Boston 8 F is installed along the conductors on the right, Flexima Boston 10 F on the left. On the control images, drainage is adequate.

After 3 days, after making sure that there were no clinical and laboratory signs of an acute infectious-inflammatory process, catheterization of the femoral artery was performed, an arterial catheter was installed at the level of the common hepatic artery, direct arteriography, recurrent portography were performed, according to which the usure of the right hepatic artery, portal vein was performed. was not clearly visualized.

Angiographic picture of a primary malignant neoplasm of the liver of a cholangiogenic nature. After the scan phase performed transarterial himioinfuziya (TAX) in a dosage of gemcitabine 1000 mg / m ² + tsistplatin 25 mg / m ^2, the 17/10/2014

After seven days on the 8th day after systemic chemotherapy TAX produced in the same manner gemcitabine 1000 mg / m ² + tsistplatin 25 mg / m ^2, the 10/25/2014

The patient was discharged from the hospital on October 28, 2014 in satisfactory condition.

After 21 days from the previous systemic chemotherapy, another cycle of systemic chemotherapy was carried out according to the same scheme on November 16, 2014, in a day hospital.

Subsequently, the patient was re-hospitalized at the N.N. ac. A.M. Granova 12/04/2014

On December 5, 2014, PDT was performed according to the previous method.

On December 9, 2014, direct arteriography was performed from the level of the common hepatic artery, recurrent portography, according to which a decrease in the degree of usuration of the right hepatic artery, an improvement in the patency of the trunk and branches of the portal vein were noted.

09.12.2014 made of transarterial himioinfuziya (TAX) of the former scheme gemcitabine in a dosage of 1000 mg / m ² + tsistplatin 25 mg / m ^2. On

On December 17, 2014 (8th day), a cycle of systemic chemotherapy was carried out according to a similar scheme.

On December 22, 2014, the patient was discharged in satisfactory condition.

On January 8, 2015, the next cycle of systemic chemotherapy was carried out in a day hospital according to the previous scheme.

On January 23, 2015, the patient was hospitalized at the N.N. ac. A.M. Granova to continue treatment. The next PDT session was carried out on January 27, 2015, TAX was carried out according to the same scheme on January 31, 2015.

On 02/08/2015, systemic chemotherapy was carried out similarly to the previous ones.

On February 16, 2015, a control computed tomography of the abdominal and chest organs with intravenous contrast was performed - there were no signs of disease progression in the form of distant, intrahepatic metastasis, and no increase in tumor size was found. A decrease in the size of the tumor to 46 × 9 mm was noted.

02/17/2015 tumor marker Ca19-9 in the blood - 10 IU / ml.

02/19/2015, the patient was hospitalized in the surgical department of the clinic of the Federal State Budgetary Institution "RNTSRKhT im. ac. A.M. Granova "in order to perform surgical staging and exclude carcinomatosis.

On February 20, 2015, a laparoscopic revision of the abdominal organs was performed, no signs of carcinomatosis, no intrahepatic tumor spread were detected. And a biopsy of the enlarged lymph nodes of the hepatoduodenal ligament zone was performed.

According to the histological report of February 24, 2015, there were lymph nodes of the hepatoduodenal ligament without tumor elements. Taking into account the stabilization of the tumor process, the patient was included in the waiting list for liver transplantation.

On February 25, 2015, the patient underwent orthotopic liver transplantation according to the classical technique with choledochojejunostomy on the Roux-off loop of the small intestine. The postoperative course is smooth.

03/23/2015, the patient was discharged in satisfactory condition under the supervision of an outpatient transplant center.

Currently, with a follow-up period of 4 years, according to laboratory, instrumental and imaging research methods, no recurrence of the disease has been identified.

The proposed method has been successfully used in 5 patients, three of whom have already undergone liver transplantation, while they did not have a relapse and progression of the disease, as well as post-transplant complications both in the early and in the long-term period. Two patients are on the waiting list for liver transplantation and receive treatment according to the indicated scheme.

The proposed method, in comparison with the known ones, has a significant advantage, which consists in the fact that it allows the treatment of HCC in patients who previously could not perform radical intervention by resection of the liver and extrahepatic bile ducts, tk. they belong to an unresectable group of patients, and the method developed by us allows us to reduce the general toxic effect on the patient's body, to suspend tumor growth and to achieve significantly better results (compared to the prototype) with liver transplantation in this category of patients.

The method was developed in the group of transplant surgery "FGBU RNTSRKhT" and has now been clinically tested in 5 patients with a positive result.

Claims (1)

A method for the treatment of unresectable hilus cholangiocarcinoma, including the selection of patients according to the Bismuth-Corlett IV or IIIa, or IIIb type with contralateral damage to the vascular structures, carrying out systemic chemotherapy, surgical staging and liver transplantation, characterized in that in addition to the patient before the systemic chemotherapy, targeted photodynamic therapy and no earlier than 3 days transarterial chemotherapy singly drugs cisplatin in an amount of 25 mg / m ^2, and gemcitabine in an amount of 1000 mg / m ^2, and systemic chemotherapy is carried out not earlier than 7 days after transarterial chemotherapy in the same modes once, repeating it is not earlier than 21 days, after which the specified treatment is repeated 18 days later in the same regimes at least 3 times before surgical staging, with the continuation of treatment until liver transplantation.