COMBINED TREATMENT FOR LOCALLY ADVANCED CHOLANGIOCELLULAR LIVER CANCER – THE CASE REPORT

Liver resection is the standard in the treatment of patients with the local uncomplicated intrahepatic bile duct cancer. Systemic chemotherapy is prescribed in the presence of distant metastases. Difficulties in a choice of the treatment method come up when one or several factors are revealed: the tumor spread towards the surrounding structures, multiple liver lesions, lymph nodes involvement signs. The complications presence manages treatment strategy too. The case describes the possibilities of an individual multimodal approach in a treatment strategy for the patient with locally advanced liver cholangiocarcinoma complicated by obstructive jaundice, cholangitis, cholangiogenic abscesses. The surgical approach was approved as the main one. Methods of interventional radiology, chemotherapy, radiation therapy were applied when necessary. The mentioned above treatment strategy allowed us to achieve good results in this difficult clinical case. The patient is alive for more than four years from the time of surgery, signs of progression are not currently defined.


INTRODUCTION
Liver resection with dissection of regional lymph nodes in compliance with radicalism principles still remains the preferential treatment option for the patients with intrahepatic bile duct cholangiocarcinoma [1]. Extensive liver surgery (70%) is often required to increase radicalism as well as resection of extrahepatic bile ducts (20%) and general vessels (5%). However the frequency of nonradical surgery even in these cases reaches 15% [2]. The involvement of extrahepatic bile ducts and large vessels most often occurs if portal type of liver cholangiocarcinoma is observed, for which, infiltrative periductal growth, presence of mechanical jaundice and a high frequency of postoperative complications are typical in distinction from peripheral type [3].
In inoperable cases the methods of local or regional impact, radiotherapy or systemic treatment can be applied which may converse the tumor into a resectable condition [4,5]. The search for optimal schemes and regimen of additional treatment is managed to improve the results of surgical treatment following the radicalism principles [4].
Biopsy probe histological examination depicted tumor cells growth, the structure of which was most appropriate to low-grade cholangiocellular carcinoma. Immunohistochemical examination also revealed cholangiocellular carcinoma.
Complex diagnostic examination showed no sign of distant expansion of the tumor.
The local impact methods were doubtful on the first stage because of suspicion to hilar lymph node metastases. Low frequency of objective response to systemic treatment for cholangiocarcinoma, as well as high risk of the further obstruction of sectoral and segmental bile ducts with progression of cholangitis and cholangiogenic abscesses were taken into the account when it was decided to perform extensive right hemihepatectomy added by resection of extrahepatic bile ducts as the first stage of the combined treatment for this patient. It required to perform additional separate drainage of right and left bile ducts. Firstly, on the 26th of February 2015 -right lobe ducts were drained ( fig.2.1) to decrease clinics of cholangitis and After preoperative preparation laparotomy was performed on the 19th of march 2015 which revealed the tumor mass up to 60 mm in the central part of the liver invading the bile ducts starting from the gallbladder duct completely to the liver parenchyma and also enlargement of regional lymph nodes up to 25 mm (hepatoduodenal ligamentum region, behind the pancreatic head, along common hepatic artery). Extensive right hemihepatectomy was performed with 1st segment dissection added by resection of the extrahepatic bile ducts, cholecystectomy, dissection of lymph nodes of hilar zone, along common hepatic artery, behind pancreatic head and around the celiac trunk region. During liver parenchyma resection there was observed pus coming from the crossection of widened bile ducts. Left extrahepatic bile ducts were resected 2 mm distal to the 2nd and 3rd ducts confluence: duct stump diameter was 4 mm, sectoral ducts diameter was up to 2 mm. In the crossed left lobe ducts there was also observed pus. Express histological exam of the dissected retropancreatic lymph node revealed metastatic adenocarcinoma cells. Microscopy of bile ducts resection borders showed no sign of tumor. It was decided to stitch the bile duct stump tightly because of absence of conditions to create a reliable biliodigestive anastomosis simultaneously according to severe cholangitis clinics and high bile ducts resection level. External cholangiostoma was left to assess biliary decompression. The rear wall of the pyloric portion of the stomach and duodenum bulb were mobilized and attached to liver capsule next to the stitched bile duct stump to perform an interventional biliodigestive anastomosis later.
Hystological conclusion: liver tumor mass up to 50 mm with several satellite nodules up to 5-10 mm is presented by poorly differentiated cholangiocarcinoma cells invading intrahepatic bile ducts; 3 of 11 examined lymph nodes also have metastatic cholangiocarcinoma cells (one node taken from hepatoduodenal ligamentum zone, tworetropancreatic). Microscopy revealed lever resection border invasion near the resected bile duct. 1st segment parenchyma was intact; the proximal and distal borders of the resected bile ducts showed no sign of tumor cells.
During April till September 2015 according to non-radical surgery type (R1) and lymph node involvement the patient underwent 6 courses of systemic chemotherapy repeating each 28 days in the following regimen: gemcitabine 1000 mg/m2 intravenously at 1st, 8th and 15th day, capecitabin 1600 mg/m2 daily on the 1st-14th days. Hematological toxicity of the 3rd grade (thrombocytopenia, neutropenia, anemia) was observed between courses.
Control complex examination after three courses of systemic chemotherapy on the 14th of July 2015 (including abdominal MRI with contrast enhancement and chest x-ray) revealed no sign of progression. Tumor marker levels (CEA, CA-199) were within normal values. It was decided to create an interventional puncture biliodigestive anastomosis. Previously fixed portion of duodenum was punctured through the bile duct stump with 20G needle under fluoroscopic guidance. The confirmation of the needle tip in the cavity of the hollow organ was obtained. After that 0,038 J-conductor was put through the needle by which a manipulative 5F catheter was introduced ( fig.3.1). The next step was a 7F cholangiostomic catheter installation ( fig.3.2) to manage external-internal pass.
The complex control examination held on the 10/06/2015 (including abdominal MRI with contrast enhancement and chest CT) showed no sign of tumor progression. Inhomogeneity of liver parenchyma was noted with thickening of soft tissue around the bile duct stump. The stump caliber was 6 mm, segmental ducts -3 mm. Tumor marker levels: CEA = 2,0 ng/ml, CA-199 = 15,0 U/ml. Control cholangiogram from 11/02/2015 demonstrated adequate bile drainage function thus 7F catheter was replaced by 12F one with the source imitator ( fig.3.3.) installation to perform intraductal radiotherapy as the next step in combined treatment strategy.
From 11/02/2015 to 11/19/2015 in order to reduce the risk of continued tumor growth in the area of microscopically nonradical surgery (liver parenchyma near the intersection of the left bile ducts) intraductal radiotherapy was performed on the left lateral sectoral and 3rd segmental ducts (from the 1st to the 7th mark, the length of the active line was 50 mm, the distance from the center of the source was 10 mm, fig.3.3). An 18-channel microSelectron HDR device was used for the radiotherapy. Ir192 was a source of radiation with a normal activity of 10 Ci. Twelve sessions of 4 Gy were performed, the course dose was 60 Gy by the isoeffect.
In case of a very high probability of post-beam stricture of biliodigestive anastomosis development as well as tumor relapse risk -cholangiostomic drainage was kept until June 2017 to prevent obstructive jaundice. The drainage was changed each 3 month with checking of its location and correction if necessary. The internal part of the drainage was located in the duodenal bulb cavity, the external end was blocked.
Complex control examination data from 03/14/2018 (including abdominal MRI with contrast enhancement and chest fluoroscopy) showed no sign of tumor progression. Duodenoscopy revealed bile admission through a tiny defect in the upper duoudenum bulb wall.

DISCUSSION
Surgical treatment is a potentially radical method for intrahepatic bile duct cancer patients. It is reasonable to value the use of local destruction methods or radiotherapy variety, as well as chemoinfusion or hepatic artery chemoembolization, and, finally, -systemic chemotherapy in case if surgery is impossible [4].
In case of little tumor size with isolated liver lesion the usefulness of surgery usually leaves no doubt. The prevalence of systemic chemotherapy in case of hematogenous or implant metastases is also obvious. Treatment strategy for patients with no sign of distant tumor metastases but having such negative prognostic factors as lymph node metastases, multiple liver lesions, vessel and/or extrahepatic bile ducts invasion with obstructive jaundice development still remains discussable [1].
In such cases the current conservative treatment strategies with application of radiotherapy, systemic and regional chemotherapy attract firstly by their relative safety and by increasing effectiveness [6,7,8]. Combination of gemcitabine, cisplatin and nab-paclitaxel allowed to reach a partial answer to therapy in 45% of cases [9]. For some of the previously inoperable patients (12.5-36.4%) liver resection can be performed after induction chemoradiotherapy is applied and then, in R0-surgery cases it can help to achieve survival results comparable to the ones for primary resectable cases [5,10].
Taking a review of the presented case it's worth noting that the usefulness of preoperational therapy was also discussed. Such factors as reasonable doubt in surgery radicalism and lymph node enlargement revealed by MRI pushed to use preoperative therapy however, there was no confidence that chemotherapy would be provided completely taking in account BMI < 15 and a source of infection existence (cholangitis and cholangiogenic abscesses) which was significantly hard to sanitize. It is also important to underline that the actual chemotherapy regimen for cholangiocarcinoma patients in 2014th year was gemcitabine and cisplatin combination: in case of its usage only 19% of objective answer was expected and less than half of patients included in the cited study managed to finish the complete course [11].
The presence of enlarged lymph nodes suspicious to be metastatic in liver hilar region, behind pancreatic head and along common hepatic artery made the usefulness of local or regional therapy methods very doubtful. Persistence of infection in the undrained liver segments leading to cholangiogenic abscesses formation also significantly reduced the safety of these methods. During surgery lymph node metastases were proved as well as persistence of purulent cholangitis in spite of separate bilateral bile ducts drainage performed. According to mentioned above reasons it was decided not to perform reconstructive step on site of surgery which required further creation of an interventional biliodigestive anastomosis.
Because of poor results of surgical treatment for cholangiocarcinoma patients, the search for effective methods of additional therapy is justified. Preoperative therapy in inductive variety was discussed above while neoadjuvant treatment in case of deliberately resectable tumors is not recommended [12]. Standard adjuvant chemotherapy for biliary cancer patients is presented by capecitabine usage in monoregimen after BILCAP work is published [13]. There are no randomized trials which demonstrate the advantages of other schemes in adjuvant regimen compared to common cohort [14], but their usage can be justified in case of unfavorable factors are revealed [15,16].
By the way, we could not rely on the above-mentioned modern sources at those time, however, taking into account nonradical surgery results the usefulness of postoperative treatment was doubtless; besides that, Murakami et al. suggested that addition of adjuvant chemotherapy improves the long-term survival results in lymph node invasion patient group [17]. In order to reduce the risk of distant progression chemotherapy was performed for 6 month in combination of gemcitabine and capecitabine. Intraductal radiotherapy was performed on the left lateral sectoral and 3rd segmental ducts (the area of maximum local relapse risk) after the systemic treatment and exception of further tumor progression according to abdominal MRI and chest CT data were finished. This type of radiotherapy was chosen for its maximum safety and accuracy of impact.
By the time of publication (4 years after the surgery) the patient is alive and has no complaints. ECOG 0, weight 42 kg, BMI = 17.7. Clinical and diagnostic examination data show no sign of tumor progression.

CONCLUSION
Reported clinical case demonstrates the result of successful use of individual combined treatment strategy for the patient with cholangiocellular liver cancer with extrahepatic bile ducts and regional lymph nodes invasion. Interventional methods were used to reduce the clinics of jaundice and cholangitis, biliary reconstruction and radiation source admission. Surgical stage was presented by R1-extensive resection. Systemic chemotherapy scheme selected in account with available at the time information sources and drugs as well as intraductal radiotherapy use allowed to reach good results in the difficult clinical condition: by the time of the article preparation (May of 2019) the patient was alive and had no sign of tumor progression.