REGIONAL CHEMOTHERAPY AS AN OPTION FOR TREATING UNRESECTABLE CHOLANGIOCARCINOMA BY: IRENA PEJCIC – UNIVERSITY OF BELGRADE

Regional Chemotherapy as an option for treating unresectable cholangiocarcinoma

By: Irena Pejcic – University of Belgrade 

Introduction

Bile duct cancer, also referred to as cholangiocarcinoma, is a rare malignancy. The illness itself is troublesome to diagnose and is typically fatal because of its late clinical presentation and fast turnover.

According to the World Health Organization[1], these tumors arise from epithelial cells involving the intrahepatic, perihilar or distal biliary tree. The bile duct plays an important function in draining the bile from the liver into the small intestine.  This is the second most common primary hepatic malignancy with over 90 percent of the cholangiocarcinomas being adenocarcinomas, while the rest are diagnosed as squamous cell carcinomas. Thus, we can divide the adenocarcinomas into 3 subtypes: nodular, sclerosing and papillary. Several risk factors have been associated with cholangiocarcinoma including parasitic infections, primary sclerosing cholangitis, hepatolithiasis and a variety of toxins. On the other hand, there has been an increased link between cholangiocarcinoma and lifestyle risk factors such as diabetes, obesity and alcohol consumption[2]. Furthermore, increased body mass index has also proven to have a signification association with cholangiocarcinogenesis[3].

Over the last decade the reported incidence of cholangiocarcinoma in North America has been increasing considerably. There are approximately 5000 new cases per year with men having a greater mortality rate than women (1.9 and 1.5 per 100,000, respectively)[4].
The most common occurrence is in the 6th to 7th decade of life and the vast majority of patients with unresectable tumors die between 6 months and 1 year following diagnosis.
A variety of imaging techniques such as MRI, CT scan and tissue biopsy of the lesion are used to confirm the diagnosis of cholangiocarcinoma. It is not uncommon for metastases to occur in the regional lymph nodes and the bordering organs. However, even though distant metastases are rare they may involve bone, muscle, brain and endocrine glands. If patients are diagnosed early on with cholangiocarcinoma surgical resection would be the first line treatment.  Unfortunately, considering it is usually characterized by late diagnosis there is an increased chance that the tumor is unresectable. In those cases, patients could be treated with endoscopic or percutaneous stent procedures. In advanced metastatic disease, the standard palliative treatment remains chemotherapy with Gemcitabine and Cisplatin. However, studies show that there is insufficient benefit from administering palliative chemotherapy due to the low survival rates.[5]

Case Report

The case managers at Rupert Case Management (RCM) saw a 60 year old Caucasian male who presented with vague epigastric discomfort and heart burn. Initially, he was sent for an abdominal ultrasound that showed an intrahepatic biliary dilation along with an enlarged heterogenous liver with two suspected solid lesions. Investigation of the patient’s bloodwork revealed elevated bilirubin and alkaline phosphatase. The rest of the blood findings were within normal ranges. On examination a month later he presented with jaundice, darkened urine, lightened stool, persistent nausea and a 10 lb weight loss. At this time blood work revealed elevated liver function tests.

The abdominal/pelvic computed tomography, showed a presence of a 6.6 x 9.9 x 13.1cm ill-defined lesion occupying majority of the left lobe of the liver. The common bile duct and the cystic duct were very narrow, leading to the suspicion of cholangiocarcinoma. The endoscopic retrograde cholangiopancreatography (ERCP) was performed which confirmed a complicated hilar structure while cytopathology was positive for adenocarcinoma. ERCP was repeated and it showed a stricture at the bifurcation with complete occlusion of the left liver lobe. The patient had a stricture of the proximal right hepatic duct that resulted in upstream dilation. Hence, a 12 cm 7 French stent was deployed and good drainage was recovered. After his diagnosis of cholangiocarcinoma was confirmed, the patient was seen by a hematologist and a transplant surgeon who offered potential surgical options only after completing 3 cycles of systemic chemotherapy. He received 3 cycles of Gemcitabine and Cisplatin for 2 months. Unfortunately, chemotherapy was stopped due to a formation of a liver abscess. After the ultrasound guided drainage was completed he resumed chemotherapy with little success. During this period his chemotherapy was stopped a few more times due to thrombocytopenia. In total, he completed 5 cycles. Another CT scan was done which noted that the atrophic left lobe of the liver was replaced by the tumor extending into segment 8 of the right lobe of the liver. There was evident involvement of the left portal vein, left and middie hepatic veins with extent to the confluence of these vessels within the inferior vena cava. Additionally, enlarged periportal and retroperitoneal lymph nodes were observed. At the beginning of March, he was reassessed by the transplant surgeon who felt that surgery was still not an option due to the increasing lymphadenopathy and soft tissue extension around the vessels. These findings were suspicious for metastases as well as infiltrate spread.

At this point, case managers at RCM recommended Guardant 360, a blood test that provides a comprehensive summary of somatic alterations and their associated treatment options. This tumor sequencing blood test includes isolating circulating tumor DNA in order to identify the alterations in the tumor genomic panel[6]. In this patient, there was only 1 mutation found, TP53, which is an important tumor suppressor gene that is commonly seen in advanced cancers. Currently, only clinical trials are available for targeting this mutation. Thus, there are no approved drugs on the market yet.

A CT scan performed in May, confirmed a large left cholangiocarcinoma with no change in size following chemotherapy. While the metastatic lymphadenopathy didn’t significantly change a node in the posterior mediastinum was slightly sacrificed. Furthermore, a follow-up endoscopic procedure with biopsies was conducted. The case managers at RCM had contacted Dr. K.R. Aigner in Germany for a further consultation on his current medical status. Regional chemotherapy was offered as a positive alternative therapy to systemic chemotherapy. This regional chemotherapy targeted the para aortic lymph nodes attempting to get a better therapeutic response. If a positive response was elicited, the lymph nodes would necrotize and the patient could be a potential surgical candidate. The patient was advised to undergo 2-4 cycles every 3 weeks with upper abdominal perfusion through the groin access. He underwent 3 cycles of regional chemotherapy which included isolated upper abdominal perfusion through the right femoral artery and vein with Cisplatin and Novantron and simultaneous chemofiltration.

Regional chemotherapy is strictly localized to one area of the body or one particular organ. The chemotherapeutic agent is administered into the arteries supplying the tumor, aiming to produce maximal damage to the tumor while producing minimal side effects to the patient’s whole body. It has been noted that in order to permanently destroy a solid tumor, the concentration of the medication administered is 6 times higher than the dose given with conventional medication. The prognosis of successful therapy is determined by the tumor’s blood supply. Dr. K.R. Aigner, director of Medias Klinkum, recommended isolated perfusion as part of the surgical procedure for this patient. A high concentration of Cisplatin and Novantron were administered through the right femoral artery and vein while simultaneously undergoing chemofiltration. Upon completing 4 cycles of regional chemotherapy a successful decrease in Carbohydrate 19-9 (CA 19-9), a tumor marker, from a high of 23,000 down to 650 and a slight increase in liver function tests were observed.

In conclusion, Rupert Case Management experienced a complex case of cholangiocarcinoma that responded to regional chemotherapy. There is a significant need to improve prognosis and clinical outcomes in patients with unresectable cholangiocarcinoma by advancing chemotherapy and developing new strategies for treatments.

[1]  Nakanuma Y, Leong AS, Sripa B(2000) Intrahepaticcholangiocarcinoma. In: Hamilton SR, Aaltonen LA(eds.) Pathology and Genetics of Tumours of the Digestive System. World Health Organization Classification of Tumours. Lyon: IARC Press.

[2] Lepage C, Cottet V, Chauvenet M, Phelip JM, Bedenne L, Faivre J, Bouvier AM. Trends in the incidence and management of biliary tract cancer: a French population-based study. J Hepatol. 2011;54:306–310. [PubMed]

[3] Shaib YH, El-Serag HB, Nooka AK, Thomas M, Brown TD, Patt YZ, Hassan MM. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a hospital-based case-control study. Am J Gastroenterol. 2007;102:1016–1021. [PubMed]

[4] CCA: The statistics. Retrieved from http://worldcholangiocarcinomaday.org/the-statistics/ (2016. January 18)

[5] Bayraktar, S., Bayraktar, U. D., & Rocha-Lima, C. M. (2010). Recent developments in palliative chemotherapy for locally advanced and metastatic pancreas cancer. World journal of gastroenterology16(6), 673-82.

[6] Circulating tumor DNA (ctDNA) as a molecular monitoring tool in metastatic breast cancer (MBC) Austin LK, Fortina P, Sebisanovic D, Diew L, Zapanta A, Talasaz A, Cristofanilli M, J Clin Oncol 32:5s, 2014 (suppl; abstr 11093).

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