RU2753402C1 - Method for photodynamic therapy in the treatment of unresectable adenocarcinoma of extrahepatic bile ducts - Google Patents

Abstract

FIELD: medicine; oncology.

SUBSTANCE: invention relates to medicine, namely to oncology; it can be used for photodynamic therapy (hereinafter – PDT) in the treatment of unresectable adenocarcinoma of extrahepatic bile ducts. To do this, before performing intraductal PDT, a catheter with a cylindrical diffuser is inserted into the affected bile duct. An obturator is previously removed from its distal part, X-ray negative light-optical gel is extracted from the diffuser with an injection needle with the formation of a cavity of no more than 5 mm, into which a water-soluble iodine-containing contrast agent is injected. After that, the distal part of the catheter is closed with the obturator, light guide with a direct radiation output is inserted into the proximal part of the diffuser to X-ray negative light-optical gel and further, but not more than 3 mm. After that, the hollow proximal part of the diffuser is filled with the same contrast agent. Then, external-internal cholangiodrainage is installed to a patient, the diffuser is removed along a channel formed by the drainage, introduced into bile ducts, comparing the X-ray-negative part of the diffuser with the tumor, and its targeted intraductal PDT is carried out. PDT is repeated every 8 weeks until a response to the treatment is achieved.

EFFECT: method allows one to improve the selective delivery of laser radiation to the tumor due to its targeted uniform distribution along the circumference of walls of bile ducts, which significantly increases the efficiency of PDT.

1 cl, 1 ex

Description

The invention relates to medicine, more precisely to oncology and can be used in the treatment of tumors of the bile ducts, including those complicated by obstructive jaundice.

Malignant tumors of the bile ducts are an urgent problem in biliary surgery. Adenocarcinoma of the extrahepatic bile ducts (Klatskin tumor) accounts for 70-80% of cases of bile duct cancer and about 15% of all malignant liver tumors [Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007; 245: 755-762.]. Tumors of bile duct confluence present certain difficulties for surgeons, which is associated with the complexity of the operation, especially when the neoplasm spreads to the hepatic artery and portal vein. As a result, radical operations are possible only in isolated cases. The spread of the tumor of the common hepatic duct to the area of confluence with the capture of both lobar ducts of the liver does not allow reaching the "clean" edge of the resection, which leads to frequent recurrence of the tumor or the continuation of its growth. Liver transplantation is performed in a small number of Klatskin tumor (OC) patients worldwide due to rapid peripheral invasion and metastasis of the tumor, and palliative treatments such as radiation therapy or systemic chemotherapy are ineffective.

The use of drainage operations in obstructive jaundice in combination with subsequent regional chemotherapy improves the quality and life expectancy of patients. At the same time, the five-year survival rate for type IV OK according to Bismuth-Corlett is extremely low or absent.

Today, the development and implementation of new, high-tech methods for early diagnosis and treatment of OC is an urgent task.

As a rule, detecting OK at an early stage is an extremely difficult task and is carried out by chance during a dispensary examination. In view of this, most patients are admitted to the clinic already in the late stages of the disease, which do not imply radical removal of the tumor.

With unresectable forms of OK, it is possible to carry out systemic or regional chemotherapy, radiation therapy, which only slightly improve survival rates. [Clinical guidelines "Cancer of the biliary system" 2017.]

It is known that in the treatment of unresectable OC, along with traditional chemo- and chemoradiation therapy, photodynamic therapy (PDT) has been successfully used in recent years.

PDT is a binary method of treatment that involves a relatively selective accumulation of a chemical agent called a photosensitizer by a pathological tissue (tumor with a zone of perifocal inflammation), followed by activation of the accumulated photosensitizer with the help of light, which triggers a cascade of intracellular reactions leading to the death of the tumor cell. The antimicrobial and immunological effects of PDT are also components of the therapeutic effect. PDT has established itself as a method of treating tumors of almost all major localizations in the form of an independent method, as well as in combination with traditional treatments (surgical, chemotherapy and radiation therapy). Depending on the stage, nature and form of tumor growth, various options for laser irradiation have been developed to increase the efficiency of PDT. The issue of selective delivery of laser radiation to hard-to-reach tumors remains important. Considering that the method is palliative in nature, it is essential to deliver the radiation source using minimally invasive techniques. In the case of the treatment of tumors accessible to visual examination (bladder, stomach, esophagus, etc.), the light guide is delivered through an endoscopic instrument under the control of the eye.

In case of tumor lesion of the bile tree, photodynamic therapy is performed using interventional radiological techniques and under fluoroscopic control.

Being engaged in the professional treatment of patients with unresectable OC, we came to the conclusion that the selectivity of delivery of radiation without refraction, shading or reflection of a light wave in the bile ducts affected by the tumor is fundamental for the effective performance of PDT in such patients.

This prompted us to develop a fundamentally new approach to PDT in the treatment of unresectable OC.

The closest to the proposed one is "Methodology and immediate results of percutaneous endobiliary photodynamic therapy of inoperable patients with gilus cholangiocarcinoma", described in the abstract of Ph.D. thesis D.Yu. Frantseva, 2020, Moscow.

The work noted that endobiliary PDT was performed by percutaneous transhepatic access in an X-ray surgical operating room under local anesthesia with additional intramuscular anesthesia with narcotic analgesics. For intraductal photo exposure, a programmable laser surgical device "LAKHTA-MILON" with photodynamic and hyperthermal exposure modes was used. On the day of surgery, patients underwent intravenous jet injection of a chlorin-type photosensitizer (Photolon, Photoditazin, Radachlorin) at a dose of 0.4-2.2 (median 0.9) mg / kg body weight 2-5 (median 4) hours before photoactivation. Further, in the conditions of the X-ray surgical operating room, the previously installed cholangiostomy drains were replaced along the guidewire with a special delivery device, which was a transparent catheter (outer diameter 7 Fr) with an X-ray contrast label and an "open" end end, developed in our own laboratory in 2016 together with the company "Minimally invasive technologies" (LLC "MIT", Zheleznodorozhny, RF). The X-ray contrast mark of the catheter was positioned at the “start point” corresponding to the distal end of the tumor stricture. The delivery device was fixed to the skin at the puncture site and filled with saline, its proximal end was connected to the Y-adapter, which facilitated the positioning of the light delivery device in it, made it possible to reliably fix the light guide, preventing its dislocation during breathing, and also created optimal conditions for rapid flushing. internal lumen of the catheter and restoration of the optically transparent medium. As a light source, we used fiber-optic fibers with a diameter of up to 600 μm with a scattering part (diffuser) of 2, 3, or 6 cm in length, performing cylindrical light scattering. The length of the diffuser was selected individually depending on the extent of the lesion based on the data of preoperative diagnostics (magnetic resonance imaging, magnetic resonance cholangiopancretography and antegrade cholangiography). The light guide was installed in the light delivery device in such a way that its distal end corresponded to the X-ray contrast mark (“start point”). After adequate installation of the light delivery device in the lumen of the bile ducts and positioning of the light source (optical fiber) in it, the procedure was regarded as technically successful.

However, it is known that the assessment of the objective response of OK to endobiliary PDT is such a difficult task that the majority of researchers refuse it, suggesting to rely only on survival rates when monitoring effectiveness. In this work, for the first time, it is proposed to use MRI as a method for assessing the direct effects of photoinfluence, which allows, due to the high contrast of soft tissues, to register periductal changes at different times after the intervention.

Based on the results obtained, reproducible criteria for assessing the effects of intraductal PDT in OC were developed for the first time. Evaluation of an objective response using such a generally accepted criterion as tumor size initially seemed to be the simplest and most rational solution. However, it turned out that the size criterion worked well only in patients with such forms of hylus cholangiocarcinomas, in which the volumetric component could be measured independently of the portal structures, i.e. with papillary and nodular types of tumors, which, unfortunately, constituted a minority of observations. In 88% of patients included in the study, OK was presented by the periductal-infiltrative type, which generally corresponds to the literature data. As a result of the analysis of the data obtained, the authors noted the following statistically significant changes: 1 month after endobiliary PDT, there was a decrease in the largest transverse size of the tumor infiltrate at the level of the proximal hepaticoholedochus. In turn, by 4 months after the photo session, a significant increase in the longitudinal size of the summation "stellate" infiltrate was noted at the level of the confluence of the lobar bile ducts, which, in our opinion, indicated the need for repeated PDT at an earlier date.

Thus, the prototype method, which consists in the delivery of light into the bile ducts, followed by the excitation of the photosensitizer and the activation of the photochemical reaction and used for the implementation of the antitumor effect, does not provide, in our opinion, a sufficient effect from the PDT.

This method has a number of objective disadvantages:

- the selectivity of the positioning of the device for radiation is not controlled radiographically (only the distal part of the fiber is visualized), which does not allow uniformly affecting the entire area affected by the tumor;

- hit of biological fluids on the surface of the optical fiber during irradiation leads to carbonization of the emitter, thereby reducing the radiation power;

- the material of the transparent catheter, used to deliver optical fiber into the bile ducts, reduces the power of radiation absorbed by the tumor, emanating from the surface of the cylindrical diffuser;

- lack of data on the interval between PDT courses and / or their necessity.

All these disadvantages, in our opinion, significantly worsen the results of PDT in the treatment of OC.

The technical result of the present invention is to increase the efficiency of PDT due to the objective selectivity of delivery of laser light to the tumor tissue and targeted uniform distribution of it around the circumference of the bile duct walls.

This result is achieved by the fact that in the known method of photodynamic therapy in the treatment of unresectable adenocarcinoma of the extrahepatic bile ducts, including the conduction through the previously installed patient percutaneous transhepatic cholangiodrainage, cholangiography fistulocholangiography followed by targeted intraductal PDT by introducing the intraductal with a cylindrical diffuser, from the distal part of which the obturator is preliminarily removed, an X-ray-negative light-optical gel is destroyed with an injection needle in the diffuser, it is removed to form a cavity of no more than 5 mm, into which a water-soluble iodine-containing contrast agent is injected, after which the distal part of the catheter closed with an obturator, a light guide with direct radiation output is introduced into the proximal part of the diffuser up to the X-ray-negative light-optical gel and further, but not more than 3 mm, after which a hollow proximal The other part of the diffuser is filled with the same contrast agent, after which the external-internal cholangio drainage installed to the patient is removed, then the diffuser is inserted into the bile ducts through the drainage channel, comparing the X-ray-negative part of the diffuser with the tumor and its targeted intraductal PDT is performed, which is repeated repeatedly every 8 weeks to achieve a response to treatment. Selective placement of a catheter with a cylindrical diffuser inside the bile ducts, directly to the tumor tissue, enhances the local cytolytic and cytotoxic effect, triggering the mechanisms of the photochemical reaction.

Removing the obturator and the light-optical gel from the distal part of the catheter with the introduction of an iodine-containing contrast agent into the formed cavity and the subsequent return of the obturator makes it possible to make the distal tip of the catheter visible under fluoroscopy.

Subsequent introduction of a light guide with an end exit of radiation into the light-optical gel allows for light scattering around the circumference of the diffuser, converting the end-to-end radiation into spherical, which is more preferable when treating tumors of the extrahepatic bile ducts.

Filling the proximal hollow part of the catheter with an iodine-containing contrast agent makes it possible to visualize the X-ray negative “working” (active) part of the device located between the proximal and distal marks.

Removal of previously installed drains allows access to the tumor, through the channels formed by the drains themselves, introduce a catheter with a diffuser precisely to the affected area of the bile tree.

Comparison of the "working" part of the catheter with a cylindrical diffuser and tumor stricture allows targeting the affected wall of the bile duct tumor, avoiding inappropriate effects on healthy or inflamed areas inside the liver. And carrying out PDT repeatedly every 8 weeks helps prevent tumor progression and achieve a response to treatment.

All this ensures the selectivity of the delivery of laser light to the tumor tissue and its targeted uniform distribution around the circumference of the walls of the bile ducts, increasing the efficiency of PDT in the treatment of OC.

The use of such a catheter with a cylindrical diffuser and the implementation of the proposed procedure showed that the implementation of PDT by the method described by us provides a positive result in the treatment of unresectable OC, including those complicated by cholangitis and / or obstructive jaundice, which was previously impossible to achieve in patients with such complications, due to impossibility of carrying out specific anticancer treatment.

The essence of the method is illustrated by examples.

Example 1

Patient S., 49 years old, has been ill since November 2015, when obstructive jaundice appeared.

From the anamnesis: according to the data of the complex examination, the enlargement of the intrahepatic bile ducts was revealed. At the same time, against the background of intensive therapy, an increase in jaundice was noted. The patient was transferred to a city multidisciplinary hospital (General Surgery Clinic of St. Petersburg State Medical Academy of Postgraduate Education), where explorative laparotomy and double external drainage of the ducts of the right lobe of the liver were performed.

10.12.15. MRI: in the projection of the liver gate, an irregularly shaped multifocal lesion with dimensions of 42 × 35 mm was visualized, propagating along the ducts from the confluence area to the lower edge of the liver, having a fairly uniform signal. The formation was intimately adjacent to the gallbladder, its upper-posterior wall was growing at a sufficient extent, as well as in the region of the bottom. The intrahepatic ducts of both lobes were dilated. The ducts are significantly deformed. The area of confluence of the lobar ducts is affected by tumor masses. The left lobar duct is 9 mm, it was cut off at the level of confluence. The right lobar duct was not traced, the segmental ducts were expanded to 6 mm. The lumen of the common bile duct was not traced for 18 mm from the confluence; it grew and squeezed the portal vein. Intrahepatic bile ducts are dilated. For 16 mm, the formation was adjacent to the inferior vena cava.

Conclusion: MRI - a picture of the volumetric formation of the hepatic gate with germination of the wall of the gallbladder, right hepatic duct, cystic duct, as well as the area of confluence. Dilation of the intrahepatic bile ducts.

01/20/2016. The patient was consulted by a chemotherapist (oncologist) at the place of residence. Due to the presence of obstructive jaundice (high level of total bilirubin), anticancer drug therapy is contraindicated.

Consultation at the Federal State Budgetary Institution RNTSRKhT is recommended.

27.01.16. The patient was admitted to the RNTSRKhT.

28.01.16. The patient underwent an operation: external-internal percutaneous-transhepatic cholangio-drainage (NCHCCD) under ultrasonographic and Rg-control of the left lobar duct. Recanalization of the tumor stricture of the right lobar bile duct followed by its external-internal cholangio-drainage.

Obstructive jaundice was arrested, the internal passage of bile was restored, without signs of cholangitis.

02/15/2016. The patient was discharged from the FGBU RNTSRKhT in a satisfactory condition under the supervision of a district oncologist with recommendations for re-hospitalization in 3 weeks to perform direct angiography of the liver vessels in order to exclude vascular invasion and the first course of regional chemotherapy.

09.03.16. The patient was re-admitted to the clinic of the Federal State Budgetary Institution RNTSRKhT.

10.03.16. The titer of the CA 19-9 tumor marker = 986 IU / ml.

11.03.16. Direct angiography was performed: no signs of vascular invasion were detected, intra-arterial (i / a) regional chemotherapy was performed according to the GemOx scheme.

03/15/16. The patient was discharged in satisfactory condition with recommendations for re-hospitalization in 3 weeks for radical removal of the tumor.

04/08/16. The patient was admitted to the RNTSRKhT clinic for surgery.

04/11/16. A laparotomy was performed. During the revision of the organs and the hepatoduodenal ligament, a stony density of tumor formation up to 4 cm in diameter was revealed, involving elements of the liver gate, invading the gallbladder. A needle biopsy of the hepatic hilum tumor was performed for histological verification. The case was found to be unresectable.

The histological conclusion from 04/14/2016 - columns of fibrous tissue with the growth of adenocarcinoma (cholangiocarcinoma).

Postoperative diagnosis: locally advanced adenocarcinoma of the common hepatic duct T ₄ N ₀ M ₀ (Klatskin Bismuth-Corlett IV tumor).

04/20/16. The patient was discharged from the Federal State Budgetary Institution RNTSRKhT in a satisfactory condition under the supervision of a district oncologist with recommendations for re-hospitalization in 3 weeks for intraductal PDT.

05/04/16. The patient was admitted to the RNTSRKhT clinic.

05/10/16. The patient underwent the first session of intraductal PDT.

A catheter with a cylindrical diffuser was introduced. The obturator was removed from the distal part of the cylindrical diffuser, the X-ray negative light-optical gel was destroyed with an injection needle in the diffuser, it was removed and a cavity of 5 mm was formed. After that, a water-soluble iodine-containing contrast agent was injected into it. Then the distal part of the catheter was closed with the same obturator. An optical fiber with direct radiation output was introduced into the proximal part of the diffuser up to the X-ray-negative light-optical gel and further by 3 mm. After that, the hollow proximal part of the diffuser was filled with the same contrast agent. Fistulocholangiography was performed through a pre-installed percutaneous transhepatic cholangiodrainage for the patient. Further, on the conductors, the external-internal cholangiodrainages of the right and left lobar ducts were removed. Through the puncture channels parallel to the conductors, alternately inside the affected bile ducts, through the channels formed by the drainages, the diffuser was introduced into the bile ducts, comparing the X-ray-negative part of the diffuser with the tumor. Intraductal PDT of the bile duct tumor was performed. After the end of the irradiation session, the optical fiber with the diffuser was removed and bilateral external-internal cholangio-drainage was restored.

05/16/16. The patient was discharged from the FGBU RNTSRKhT in a satisfactory condition under the supervision of a district oncologist with recommendations for re-hospitalization for repeated PDT sessions.

From July 2016 to March 2017, the patient received 6 more similar sessions of intraductal PDT.

A stable positive clinical and laboratory response to the treatment was noted: a decrease in the tumor-specific tumor marker CA 19-9 from 986 to 8 IU / ml, relief of cholangitis, no signs of cholestasis, a significant improvement in the quality of life (+21 kg), social and labor adaptation. The patient is recommended to consult a hepatologist surgeon to determine the tactics of further treatment.

To date, 55 patients with unresectable Klatskin's tumor have been treated with the proposed method. To date, 21 patients are alive: two of them are in remission, fifteen patients continue treatment with our proposed method, four receive alternative antitumor and symptomatic treatment. 34 patients died within 6 to 42 months. The average life expectancy was 18.3 months.

The proposed PDT method in the treatment of unresectable adenocarcinoma of the extrahepatic bile ducts has a number of significant advantages in comparison with the known ones, the main of which is an increase in the effectiveness of OC treatment by the PDT method developed by us due to the selectivity of delivery of laser light to the tumor tissue and its targeted uniform distribution around the circumference of the bile duct walls. ... This made it possible to improve the effect of the treatment, and two patients with unresectable OC even underwent liver transplantation.

The method was developed in the Department of Operative Surgery and Interventional Radiology at the N.N. acad. A.M. Granov and was clinically tested in 55 patients with a positive result.

Claims (1)

A method of photodynamic therapy in the treatment of unresectable adenocarcinoma of the extrahepatic bile ducts, including conducting through a previously installed patient percutaneous transhepatic cholangio-drainage of fistulocholangiography followed by targeted intraductal PDT, characterized in that before performing the intraductal catheteric part of the duct from the intraductal bile duct into the duct the obturator is preliminarily removed, an X-ray-negative light-optical gel is removed from the diffuser with an injection needle to form a cavity of no more than 5 mm, into which a water-soluble iodine-containing contrast agent is injected, after which the distal part of the catheter is closed with an obturator, a light guide with direct radiation output is introduced into the proximal part of the diffuser to the X-ray-negative light-optical gel and further, but not more than 3 mm, after which the hollow proximal part of the diffuser is filled with the same contrast agent, according to After that, the external-internal cholangiodrainage established to the patient is removed, then the diffuser is introduced into the bile ducts through the drainage canal, comparing the X-ray-negative part of the diffuser with the tumor, and its targeted intraductal PDT is performed, which is repeated several times every 8 weeks until a response to treatment is achieved.