Vascular complications after orthotopic liver transplantation after neoadjuvant therapy for hilar cholangiocarcinoma.

Liver transplantation after neoadjuvant chemoradiotherapy has emerged as an effective treatment for patients with localized, node-negative, unresectable hilar cholangiocarcinoma (CCA) or CCA arising in the setting of primary sclerosing cholangitis (PSC). However, concern has arisen regarding the potential for vascular complications due to high-dose neoadjuvant therapy before transplantation. We reviewed our experience with specific aims to determine the incidences of arterial, portal, and hepatic venous complications in patients transplanted for CCA compared with patients who undergo transplantation for other indications, and to describe patient outcome as a result of these vascular complications. We reviewed data for all patients who underwent liver transplantation for CCA between January 1993 and April 2006 and compared the incidences of vascular complications to whole organ and living donor recipient control groups. Sixty-eight patients underwent neoadjuvant therapy and subsequent liver transplantation. Arterial complications arose in 21%; portal venous complications arose in 22%; and overall, 40% developed vascular complications. Late hepatic artery complications occurred more often in living donor recipients transplanted for CCA compared with the living donor control group (P=0.047). Late portal vein complications occurred more often in both whole organ and living donor recipients transplanted for CCA compared with the control groups (P=0.01 and P=0.009). Hepatic venous complications were rare. Patient and graft survival were not different between CCA and control patients. Liver transplantation with neoadjuvant therapy is associated with far higher rates of late arterial and portal venous complications, but these complications do not adversely affect patient and graft survival.     

Photodynamic Therapy Provides Local Control of Cholangiocarcinoma in Patients Awaiting Liver Transplantation

Many transplant centers use endoscopically directed brachytherapy to provide locoregional control in patients with otherwise incurable cholangiocarcinoma (CCA) who are awaiting liver transplantation (LT). The use of endoscopic retrograde cholangiopancreatography (ERCP)‐directed photodynamic therapy (PDT) as an alternative to brachytherapy for providing locoregional control in this patient population has not been studied. The aim of this study was to report on our initial experience using ERCP‐directed PDT to provide local control in patients with unresectable CCA who were awaiting LT. Patients with unresectable CCA who underwent protocol‐driven neoadjuvant chemoradiation and ERCP‐directed PDT with the intent of undergoing LT were reviewed. Four patients with confirmed or suspected CCA met the inclusion criteria for protocol LT. All four patients (100%) successfully underwent ERCP‐directed PDT. All patients had chemoradiation dose delays, and two patients had recurrent cholangitis despite PDT. None of these patients had progressive locoregional disease or distant metastasis following PDT. All four patients (100%) underwent LT. Intention‐to‐treat disease‐free survival was 75% at mean follow‐up of 28.1 months. In summary, ERCP‐directed PDT is a reasonably well tolerated and safe procedure that may have benefit by maintaining locoregional tumor control in patients with CCA who are awaiting LT.     

Aplicabilidad y resultados del trasplante hepático combinado con quimiorradioterapia neoadyuvante en el tratamiento del colangiocarcinoma perihiliar irresecable

BackgroundIn 2007, a multicenter protocol was developed in Catalonia, Spain, combining neoadjuvant chemoradiotherapy and liver transplantation (LT) for those patients with unresectable hilar cholangiocarcinoma (hCCA).AimTo analyse the effectiveness of the neoadjuvant chemoradiotherapy and LT for those patients enrolled in the protocol based on intention-to-treat.MethodsObservational multicenter study which includes patients ≤ 68 years-old diagnosed with unresectable, solitary tumors ≤ 3 cm in radial diameter, without evidence of lymph node metastases. The protocol was based on a strategy of neoadjuvant therapy with high-dose radiation (45 Gy in total) plus intravenous fluorouracil (5-FU) given as a daily bolus for the first 3 days of radiation follow by oral capecitabine until transplantation. The patient was included in waiting list for LT if no evidence of disseminated disease was found.ResultsBetween 2007 and 2018, 13 patients were enrolled in the transplant protocol. Of those, 61% (8/13) of the patients were transplanted. The average time spent on the waiting list was 122 days (range 5-192). Intent-to-treat survival was 69% and 39% at one and 5 years. Post-transplantation overall survival was 87% and 62% and 29% recurrence rate at 5 years.ConclusionThe suitability of the neoadjuvant chemoradiotherapy and LT protocol was 61% in our series with long-term overall survival and should be considered as an alternative to resection for patients with localized node-negative hCCA.     

Neoadjuvant therapy in the treatment of hilar cholangiocarcinoma:Review of the literature

Cholangiocarcinoma(CCA) is a malignant tumor of the biliary system and includes, according to the anatomical classification, intra hepatic CCA(iCCA),hilar CCA(hCCA) and distal CCA(dCCA). Hilar CCA is the most challenging type in terms of diagnosis, treatment and prognosis. Surgery is the only treatment possibly providing long-term survival, but only few patients are considered resectable at the time of diagnosis. In fact, tumor's extension to segmentary or subsegmentary biliary ducts, along with large lymph node involvement or intrahepatic metastases, precludes the surgical approach. To achieve R0 margins is mandatory for the disease-free survival and overall survival. In case of unresectable locally advanced hCCA, radiochemotherapy(RCT) as neoadjuvant treatment demonstrated to be a therapeutic option before either hepatic resection or liver transplantation. Before liver surgery, RCT is believed to enhance the R0 margins rate. For patients meeting the Mayo Clinic criteria, RCT prior to orthotopic liver transplant(OLT) has proved to produce acceptable 5-years survivals. In this review, we analyze the current role of neoadjuvant RCT before resection as well as before OLT.     

Liver transplantation for hilar cholangiocarcinoma—a single-centre experience

Background

Cholangiocarcinoma is an infrequent malignancy, often unresectable at the time of diagnosis. Liver transplantation may offer a chance for cure, but results in the past have been disappointing, prompting transplant centres to adopt multimodal treatment protocols and extreme patient selection.

Purpose

This study was designed to evaluate the outcome of patients with irresectable hilar cholangiocarcinoma undergoing liver transplantation in order to determine criteria for patient selection.

Methods

We reviewed our prospective cancer registry for patients with hilar cholangiocarcinoma treated by transplantation since 1997. Data were evaluated regarding tumour location, stage, overall survival, recurrence rates and prognostic factors.

Results

Liver transplantation with lymphadenectomy was realised in 16 patients with hilar cholangiocarcinoma. Seven patients received a living donor graft. Lymph node metastases were found in eight patients with a median of 13 harvested nodes and had a statistically significant negative impact on overall survival irrespective of tumour size. Only one patient underwent neoadjuvant brachytherapy and developed fatal septic complications; 3- and 5-year survival rates were 63 and 50 % in lymph node-negative patients without neoadjuvant treatment.

Conclusions

Acceptable survival rates can be achieved by transplantation for hilar cholangiocarcinoma with lymph node metastases as the only exclusion criterion. We recommend staging laparotomy with lymphadenectomy along the common hepatic artery prior to liver transplantation.     

Hiläres Cholangiokarzinom

The increasingly performed en bloc resection of liver and hilar tumor has contributed to the improvement of long-term survival in patients with hilar cholangiocarcinoma. Based on preoperative definition of operative strategy we tried to avoid any traumatization of the hilar region. Between September 1997 and September 2002, 82 patients with hilar cholangiocarcinoma were treated at our department. Three patients were excluded from any surgery. The resection rate was 75% (59 of 79); 79% (38 of 48) of en bloc resections of the hilar tumor and adjacent liver were formally curative. The hospital mortality was 7%. The 1- and 3-year survival rates of patients after explorative laparotomy, palliative and curative resection was 27 and 7%, 67 and 26%, 89 and 45% ( p<0.001), respectively. The 1- and 3-year survival rates of patients after en bloc resection were 78 and 49%, respectively. In patients with formally curative en bloc resection ( n=38), the 3-year survival rate was 63%; in patients with N0/R0 resection ( n=31) it was 71%. Lymph node involvement proved to be the only independent prognostic marker if patients who underwent hilar and en bloc resection were included in the multivariate analysis. The R situation was the only significant predictor for patients after en bloc resection. These data justify the extended diagnostic work-up and the principal liver resection in hilar cholangiocarcinoma.     

Liver transplantation for hilar cholangiocarcinoma

Hilar cholangiocarcinoma was accepted as an indication for liver transplantation at the beginning of the transplantation era. Owing to disappointing long-term results for this indication, and in parallel, encouraging results in patients with benign disease, hilar cholangiocarcinoma has generally not been accepted as an indication for liver transplantation in recent years. To improve results, more aggressive approaches have been used: “abdominal organ cluster transplantation” and “extended bile duct resection”, which lead to increased long-term survival rates. However, with improving results after conventional extrahepatic bile duct resection in combination with partial hepatectomy, extended procedures in combination with liver transplantation never became a real option in the treatment of hilar cholangiocarcinoma. However, new awareness of liver transplantation in the treatment of this cancer has been raised for patients with hilar cholangiocarcinoma in the context of underlying liver diseases such as primary sclerosing cholangitis, which preclude liver resection. Current results show increased survival figures, in particular in well-selected patients with early tumor stages. Further improvements in long-term survival may be reached with new adjuvant and neoadjuvant protocols. Patients with neoadjuvant radiochemotherapy show long-term results similar to those for liver transplantation for other indications. Also, photodynamic therapy and the use of new antiproliferative immunosuppressive agents may be an approach for further improvement of the long-term results. Currently, liver transplantation for the treatment of hilar cholangiocarcinoma should be restricted to centers with experience in the treatment of this cancer and should be taken into consideration in patients with contraindications to liver resection.     

Radiochemotherapy and Transplantation Allow Long-Term Survival For Nonresectable Hilar Cholangiocarcinoma

Results of liver transplantation in the treatment of cholangiocarcinoma have been poor as a result of the high incidence of locoregional dissemination and tumor recurrence. This study evaluates the effect of neoadjuvant chemoradiation therapy combined with orthotopic liver transplantation in a carefully selected group of patients with hilar cholangiocarcinoma. Seventeen patients were included in the study. The neoadjuvant protocol included 6,000 cgy biliary brachy-therapy delivered through percutaneous transhepatic catheters and intravenous infusion of 5-fluorouracil (300mg/m2/day) until transplantation. Five of the 17 patients demonstrated tumor progression precluding transplantation. One patient died of sepsis on the waiting list. Eleven patients underwent liver transplantation, a median of 3.4 months (range = 1-26 months) after diagnosis. Five of the 11 (45%) are alive without evidence of tumor recurrence with a median follow up of 7.5 years (range = 2.8-14.5 years). Six deaths occurred in the transplanted patients. Tumor recurrence was responsible for two deaths at 10 and 18months, respectively, after transplantation. Three mortalities resulted from bacterial or fungal peritonitis and sepsis. One patient underwent re-transplantation for chronic rejection and died from graft failure resulting from hepatic artery thrombosis 16 months after diagnosis without evidence of tumor recurrence. Complications of transhepatic catheter placement included bile duct perforation (n = 4) and biliary-portal vein fistula (n = 1). All these patients died of tumor recurrence or sepsis. Cholangiocarcinoma should not be considered an absolute exclusion criteria for orthotopic liver transplantation. Long-term, tumor-free survival was achieved in 45% of the transplanted patients. Complications of biliary catheter placement for brachytherapy were associated with poor outcome.     

Neoadjuvant chemotherapy as a treatment strategy for multiple bilobar liver metastases from colorectal carcinoma

Hepatic resection remains the only potentially curative therapy for patients with colorectal liver metastases. Because most have multiple bilobar liver metastases, surgical resection is possible in only 25-58% of patients with colorectal liver metastases. Currently, attention is focused on the potential for neoadjuvant chemotherapy to render formerly unresectable patients resectable. The availability of more efficacious chemotherapy agents and an inventive approach to delivery schedules have resulted in an increase in the number of candidates for hepatic resection after neoadjuvant chemotherapy. Although tumor response varies with regimen and/or route of chemotherapy for colorectal liver metastases, with 16-63% tumor response rates, hepatic resection for responders after neoadjuvant chemotherapy gives survival benefits, with 20-48% 5-year survival rates after surgery. Provided that neoadjuvant chemotherapy controls multiple bilobar liver metastases well, aggressive hepatic resection should be considered for patients with those lesions. As a treatment strategy for multiple bilobar liver metastases, neoadjuvant chemotherapy is a useful to increase resection rates and may contribute to the improvement of prognosis in patients with such lesions.     

Strategy for hepatoblastoma management: Transplant versus nontransplant surgery

Background: Liver transplantation now is proposed for managing selected hepatoblastoma cases. Indications are not yet well defined. Methods: The case records of 34 children with hepatoblastoma treated over a period of 10 years (1991 to 2000) were reviewed retrospectively. Results: All patients benefited from preoperative chemotherapy. Twenty patients underwent major hepatic resections. Twelve patients, in absence of residual metastasis, underwent liver transplant because the tumour remained unresectable after chemotherapy. Two patients who presented with recurrence after a right hepatectomy, benefited from transplant as a second option. Two other patients did not undergo surgery because of widespread disease or resistance to chemotherapy. Disease-free survival rates were 95% after surgical resection, 100% when primary transplant was performed in patients with good response to chemotherapy, 60% after transplantation in patients with poor response to chemotherapy, 50% in patients with transplant as second option, and 0% in patients not undergoing surgery. Conclusions: Transplantation is a potentially curative option for unresectable hepatoblastoma when chemosensitive (decrease in alpha-fetoprotein and decrease in tumour size). In this context, also favourable cases with good response but difficult resections with doubtful margins of resection may best be proposed for primary transplantation. Patients with recurrent or resistant disease are not good candidates.     

Current status of liver transplantation for cholangiocarcinoma

Cholangiocarcinoma (CCA) is the second most common liver cancer with a median survival of 12-24 mo without treatment. It is further classified based on its location into intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA. Surgical resection is the mainstay of treatment, but up to 70% of these tumors are inoperable at the time of diagnosis. CCA was previously an absolute contraindication for liver transplantation (LT) due to poor outcomes primary due to early recurrent disease. However, improvement in patient selection criteria and neoadjuvant treatment protocols have improved outcomes for inoperable pCCA patients with recent studies reporting LT may improve survival in iCCA. Future advances in the treatment of CCA should include refining patient selection criteria and organ allocation for all subtypes of CCA, determining effective immunotherapies and the evolving role of personalized medicine in patients ineligible for surgical resection or LT. Our article reviews the current status of LT in CCA, along with future directions in managing patients with CCA.     

Resection, including transplantation, for hepatoblastoma and hepatocellular carcinoma: impact on survival.

Long-term survival in children with primary hepatic malignancies can not be expected without complete tumor resection. In the last ten years we have treated 21 children with hepatocellular carcinoma (HCC) and 21 children with hepatoblastoma (HEP), with tumor extirpation our surgical goal. Operative treatment included partial hepatectomy ([PH] 20), either primary (10) or delayed (following chemotherapy) (10), total hepatectomy and orthotopic liver transplantation ([OLT] 13), or upper abdominal exenteration and multiple organ transplantation (2). Two patients had both PH and subsequent total hepatectomy and OLT. Overall survival was 48% (20/42), with 9 patients dying of progressive disease prior to removal of their tumor. HEP patient survival was 67% (14/21), including 2 of 6 who underwent primary PH, 7 of 8 who had delayed PH, and 5 of 6 who underwent OLT. Survival for the children with HCC was 29% (6/21), including 1 of 4 after primary PH, 1 of 2 following delayed PH, 3 of 7 following OLT, and 1 of 2 after exenteration and multiple organ transplantation. Preoperative chemotherapy facilitated removal of 10 initially unresectable tumors (8 HEP, 2 HCC) at a second-look procedure. Total hepatectomy and OLT markedly improved survival in patients with disease unresectable by standard methods. Partial hepatectomy, either primary or delayed, should be attempted in all children with hepatic malignancies. Total hepatectomy and OLT appears to be a viable adjunct in the treatment of childhood malignancies, and should be used for otherwise unresectable tumors as part of a carefully planned protocol.     

Liver transplantation and tacrolimus monotherapy for hepatocellular carcinoma with expanded criteria

Liver transplantation is the only curative treatment option for patients with cirrhosis and unresectable hepatocellular carcinoma (HCC) without extrahepatic dissemination. Criteria for transplantation in HCC are controversial. In this study, we evaluate the early results of liver transplantation for unresectable HCC. Between 2003 and 2004, 10 patients (three woman, seven men; aged 1.1 to 64 years) with occult or incidental HCC underwent liver transplantation. The inclusion criteria (independent of tumor size and number of tumor nodules) were: no invasion of major vascular structures and no evidence of extrahepatic disease, including that based on hilar lymph node biopsy and cytopathological examination of intraperitoneal fluid. Eight patients (80%) received tacrolimus and two patients (20%) received rapamycin monotherapy with early withdrawal of the corticosteroid. Four patients had neoadjuvant chemoembolization before transplantation. None of the patients received adjuvant chemotherapy. Two patients with hepatitis B virus cirrhosis underwent antiviral prophylaxis with anti-HBs antibody and lamivudine. During follow-up (range, 8 to 19 months), all patients did well with excellent graft function. There was no evidence of tumor recurrence on imaging studies, and there were no elevations in alpha fetoprotein or carcinoembryonic antigen levels. Low-dose immunosuppression and expanded criteria for liver transplantation for HCC appear to have beneficial effects on disease recurrence and patient outcomes, especially in regard to living donation.     

原位肝移植联合胰头十二指肠切除根治肝门部胆管癌

目的探讨原位肝脏移植联合胰头十二指肠切除根治复杂肝外胆管癌的方法及疗效。方法结合国外临床经验和肝外胆管癌的生物学特点,对1例Bismuth-Corlette Ⅳ型肝外胆管癌侵犯肝内二级胆管及胆总管下段的患者,实施原位肝脏移植联合胰头十二指肠根治性切除。采用链霉素-卵白素-生物素（LSAB）的免疫组织化学技术,检测切除的病理标本中胆管上皮细胞角蛋白CK9和CKl7、癌胚抗原、肝细胞蛋白,确认肿瘤组织学来源。术后给予他克莫司联合甲泼尼龙片抗排斥治疗。同时,拉米夫定联合大剂量乙型肝炎免疫球蛋白静脉滴注预防乙型肝炎复发,术后定期随访。结果术后移植肝的肝功能恢复顺利,血清胃肠道肿瘤标志癌胚抗原、CA19-9、CAl25均降至正常范围。随访14个月至今,移植肝及消化功能良好,患者健康并恢复术前工作。结论对无远处转移和腹腔播散,且常规手术无法根治的浸润型肝门部胆管癌Bismuth-Corlette Ⅳ型,可考虑实施全肝、肝十二指肠韧带联合胰头十二指肠整块切除术根治肿瘤。然后行同种异体原位肝移植并重建消化道。该方法可能有利于提高肿瘤的切除率和患者长期生存率。     

Long-term survival after living-donor liver transplantation for unresectable colorectal metastases to the liver: case report

We present a case of long-term survival of a patient who underwent living-donor liver transplantation for unresectable liver metastases of colon cancer. Two years after left hemicolectomy and subsequent to repeated liver resections, this patient presented with unresectable metastatic disease confined to the liver. She was offered a living-donor liver transplantation, and her husband agreed to be the donor. Five years after transplant, she was alive and recurrence free.     

Zentrale Gallengangskarzinome

Surgical resection provides the only chance of cure for patients suffering from hilar cholangiocarcinoma. Due to the central anatomic localization within the liver hilum, established guidelines of oncologic surgery are difficult to apply. Resection of the hilar bifurcation alone or in combination with limited hepatic resection can be performed with low morbidity and low mortality but shows a high rate of local tumor recurrence. Usually, extended resection is required to achieve adequate safety margins. Right trisectionectomy complies best with the basic rules of oncologic surgery while allowing the maximum safety margin. The 5-year survival rates reported after right trisectionectomy range between 20% and 40% and reach 59% in selected patients. The increasing experience with living donor transplantation and recent advances in neoadjuvant tumor therapy may lead to renewed discussion of liver transplantation in hilar cholangiocarcinoma.     

Liver transplantation for the management of hepatoblastoma

INTRODUCTION: Hepatoblastoma (HEP) is the most frequent liver malignancy occurring in childhood. Surgical resection currently represents the gold standard for treatment. In patients with initially unresectable tumors, chemotherapy may induce remarkable reductions in size. In nonresponder patients, liver transplantation (OLTx) may offer a chance of cure. MATERIALS AND METHODS: From 1990 to 2003, a total of 400 OLTx (31 pediatric transplants) have been performed at Padua University. Seven patients (4 males and 3 females) underwent OLTx for hepatoblastoma. All patients presented with bilobar liver involvement and had received chemotherapy according to the SIOPEL-1. In all patients preoperative staging was negative for extrahepatic involvement. RESULTS: The mean age of the pts was 8.2 years (range 6.4 months to 34 years). Mean follow-up after OLTx was 41.4 months (median 36, range 3 to 108 months). Actuarial patient survival rates after OLTx for hepatoblastoma are 83.3%, 83.3%, and 56% at 1, 3, and 5 years, respectively. Five of seven subjects with HEP are alive after transplant at 3, 12, 36, 65, and 108 months. Two patients died owing to recurrent disease after 6 and 60 months, respectively, from transplantation. Another subject, primarily treated with surgical resection, shows HEP recurrence at 40 months after OLTx. The remaining 4 patients are alive and well at a mean follow-up of 28 months (median 24, range 3 to 65 months). CONCLUSIONS: Liver transplantation may represent a valid therapeutic option for patients with unresectable HEP, but it is contraindicated in cases of recurrence following previous resection surgery. Neo-adjuvant chemotherapy is of paramount importance to obtain good long-term results.     

Strategy for the treatment of unresectable hepatoblastoma: neoadjuvant chemotherapy followed by delayed primary operation or liver transplantation

We present our experience in using neoadjuvant regional and systemic chemotherapy together with surgical resection as a strategy for the treatment of unresectable hepatoblastoma. Neoadjuvant chemotherapy was given prior to surgical treatment in six children with unresectable hepatoblastoma. Furthermore, the neoadjuvant chemotherapy was intensified according to response to the initial treatment. Surgical resection was performed when the tumor was judged to be resectable. The adjuvant chemotherapy was given after delayed primary operation. Five of six children receiving neoadjuvant chemotherapy responded to the treatment and subsequently received delayed primary operation or living donor liver transplantation. All five children who had successful surgery have completed treatment and show no evidence of disease to date (27-115 months after surgery). It is concluded that neoadjuvant chemotherapy given as a combination of regional and systemic chemotherapy was effective for tumor reduction in cases with early stage or stage III disease. Also, to increase the cure rate of children with localized disease that was still unresectable after chemotherapy, living donor liver transplantation, which offers some advantage in timing of transplant compared with cadaveric liver transplantation, seems to be a possible procedure.     

Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients.

OBJECTIVE: Currently, there is considerable controversy about the place of transplantation in the treatment of hepatocellular carcinoma (HCC). This study compared resection to transplantation in cirrhotic patients with HCC in order to determine reasonable indications of each treatment. SUMMARY BACKGROUND DATA: The usual procedure is to resect when feasible and to transplant in other cases. METHODS: Three-year survival with and without recurrence was analyzed in 60 patients who underwent resection and 60 who underwent transplantation. Several prognostic factors, such as size, number of nodules, portal thrombus, and histologic form, were studied. RESULTS: In terms of overall survival rates, resection and transplantation yield the same results (50% vs. 47%, respectively, at 3 years). For transplantation, however, the rate for survival without recurrence is better than that for resection (46% vs. 27%, respectively; p < 0.05). In the case of small uninodular or binodular tumors (< 3 cm), transplantation has much better results than resection (survival without recurrence, 83% vs. 18%, respectively; p < 0.001). However, it seems that a group of patients with high risk of recurrence after transplantation can be determined (diffuse form, more than two nodules > 3 cm, or presence of portal thrombus). CONCLUSIONS: The best indication for transplantation seems to be patients with small and uninodular or binodular tumors; until now, these patients were considered to be the best candidates for resection. Patients undergoing transplantation for unresectable, large, multinodular or diffuse tumors seem to represent bad indications for transplantation. These results could help define reasonable indications for transplantation in an era with a shortage of liver grafts.     

Cholangiocarcinoma: a review of the literature and future directions in therapy

Cholangiocarcinomas (CCA) are a group of rare cancers with an incidence of about 1.26 per 100,000 people. The disease reflects one of three different subtypes: intrahepatic, perihilar or hilar and distal cholangiocarcinoma. The preferred modality of definitive therapy is surgical resection with or without adjuvant therapy, however the majority of patients with this disease do not present at an early stage. Some efforts to improve survival rates have come in the form of offering neoadjuvant therapy prior to surgical resection or liver transplantation. Some new protocols are in the process of development for neoadjuvant therapy. Despite advancements in locally advanced or borderline resectable lesions, most patient present at an advanced stage. The mainstay of treatment for advanced stage disease is chemotherapy regardless of location. The mainstay of treatment in fit patients is the combination of gemcitabine and cisplatin. The addition of nab-paclitaxel to this backbone is currently being evaluated in phase III trial. In addition, the role of targeted therapy is currently being studied extensively through multiple different mutational pathways including isocitrate dehydrogenase-1 (IDH1), fibroblast growth factor receptor (FGFR), epidermal growth factor receptor (EGFR) and ERBB2 (HER2/neu). CCA remains a significant challenge in medicine, however recent studies have shown that there is significant interest in advancing therapy in the form of neoadjuvant, adjuvant and palliative intent treatment.