Introduction

Cholangiocarcinoma (CCA), the second most common primary hepatic malignancy, accounts for 3 % of all gastrointestinal cancers and has an increasing incidence worldwide [1–3]. Several prognostic factors have been reported, including stage of disease, CA 19-9 levels, and type of treatment [4, 5]. Surgical resection has long been the mainstay of curative treatment for CCA, with 5-year survival rates of 27–48 %, but only 10–20 % of patients are candidates for resection [6–11]. Orthotopic liver transplantation (OLT) has been proposed as an alternative treatment for those patients that are deemed unresectable. OLT is able to achieve a wider excision and a more complete removal of the tumor, thereby reducing the risk of intra-operative tumor spillage. OLT is a particularly attractive option in patients with PSC or underlying liver disease as it offers a cure for both the tumor and the underlying liver disease.

The initial experience of OLT for CCA in the 1980s and early 1990s yielded dismal results, with 5-year survival rates of 5–17 % [12–14], leading many surgical centers to abandon OLT as a possible therapy for CCA [15]. In January 1993, the Mayo Clinic developed a protocol of external beam irradiation, endoluminal irradiation, chemosensitization with 5-fluorouracil, and exploratory laparotomy prior to OLT for selected patients with unresectable hilar CCA located above the cystic duct (Fig. 1) [16]. Their initial experience, published in May 2000, demonstrated a 1-year disease-free survival rate of 92 % [16]. Five-year survival rates among the 125 patients who underwent OLT for hilar CCA from 1993 to 2009 were recently reported to be 73 % [17]. These encouraging results over the past decade have revived the enthusiasm for OLT as an option for patients with hilar CCA. Although additional centers have started to perform OLT for CCA, it is unclear if these published results are generalizable or limited to the experience at the Mayo Clinic. The aims of our study were to determine 1-, 3-, and 5-year post-transplant survival rates for patients undergoing liver transplantation for hilar CCA and to identify prognostic factors affecting post-transplant survival.

Fig. 1
figure 1

Pre-transplant Mayo protocol. EUS endoscopic ultrasound, FNA fine needle aspirate, EBRT external beam radiation therapy (adapted from J Natl Compr Canc Netw 2009;7[4])

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Methods

Patients and Study Variables

This study was performed with approval of the University of Michigan Institutional Review Board. Donor and recipient data was collected from the Scientific Registry of Transplant Recipients (SRTR) database for all adult patients, 18 years or older, with a diagnosis of hilar CCA who were listed for liver transplantation between October 1987 and May 2008. The diagnosis of hilar CCA was established by the transplant center indicating the corresponding diagnostic codes in the SRTR database at the time of listing. This nationwide registry obtains transplant-related and patient-related data from the Organ Procurement and Transplantation Network (OPTN), the United Network for Organ Sharing (UNOS), and Social Security. Individual centers report the information to the OPTN/UNOS. Social Security records are utilized to verify date of death.

Demographic information including age, race, gender, ABO blood group, and history of chronic liver disease as well as laboratory data from the time of transplant including creatinine, albumin, bilirubin, INR, MELD, and MELD exception points were recorded. The transplant variables of interest included type of transplant (cadaveric vs. living-donor), cold ischemia time, incidental versus known diagnosis of CCA, history of acute rejection, immunosuppression regimen (standard vs. nonstandard), and date of transplantation. Data regarding tumor stage at diagnosis, receipt of neo-adjuvant therapy, identification of center where the transplant was performed, and post-transplant recurrence rates were not included in the database. The patients were categorized by time period, as a pre-protocol group and post-protocol group, as patients transplanted prior to May 1, 2000 were considered to be in the pre-Mayo protocol era, and those transplanted after May 1, 2000 were considered in the post-Mayo protocol era. Although the Mayo protocol was initiated in 1993, results were first published in 2000. We chose this latter time point as we were trying to determine the impact of this publication on results nationwide.

Statistical Analysis

The demographic and laboratory data, as well as transplant characteristics were compared between patients transplanted prior to 2000 and those transplanted after 2000. Chi-squared tests were used for categorical variables and t tests were used for continuous variables. Survival curves were generated using the Kaplan–Meier method and compared using log-rank test. Patients were censored at the time of death, or at the time of last data entry if they were lost to follow-up. Prognostic factors predictive of survival were identified by Cox regression analysis. A p value < 0.05 was considered statistically significant for both univariate and multivariate analyses. All analyses were performed using Stata 10.0 (College Station, TX, USA).

Results

Patient Characteristics

There were a total of 595 patients listed for a primary diagnosis of hilar CCA between October 1987 and May 2008, with 330 patients (55.5 %) undergoing transplantation. An additional 29 patients had an incidental diagnosis of CCA at the time of transplantation, and thus a total of 359 patients received a liver transplant. Eighteen patients (5 %) underwent re-transplantation—nine due to vascular thrombosis, three for primary non-function, and six for unknown causes of graft failure.

Baseline patient characteristics are shown in Table 1. The median recipient age at the time of OLT was 49 years (range 18–71). More than 90 % of patients were Caucasian and 66 % were male. One hundred twenty-one patients (34 %) had underlying chronic liver disease, with 84 (23 %) having a history of PSC. The median bilirubin at the time of transplant was 2.1 mg/dL (range 0.3–40.3 mg/dL), and the median creatinine was 0.9 mg/dL (range 0.3–4.2 mg/dL). One hundred sixty-four patients (46 %) were transplanted before the model for end-stage liver disease (MELD) score was implemented in February 2002. The remaining 195 patients had a median lab MELD score of 12 (range 6–40), with 79 (41 %) reporting MELD exception points after listing for OLT.

Table 1 Characteristics of patients undergoing OLT for CCA
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There were 150 patients transplanted for CCA prior to May 2000 (pre-protocol group), and 209 patients underwent OLT between May 2000 and May 2008 (post-protocol group). Patients in the post-protocol group were older (median 52 vs. 46 years, p < 0.01) and more likely to be male (71 vs. 59 %, p = 0.02). There were similar rates of underlying liver disease (p = 0.72) and PSC (p = 0.14) between the two groups. The post-protocol group had a higher rate of nonstandard immunosuppression (42 vs. 4 %, p = 0.01) and higher rates of acute rejection (4.3 vs. 0 %, p = 0.16). Three hundred nineteen recipients (88 %) received whole cadaveric allografts, 40 (11 %) received allografts from living donors, and five patients (1 %) received split cadaveric allografts. All of the living donor transplantations occurred in the post-protocol group. Recipient laboratory values at the time of transplantation including creatinine, albumin, and total bilirubin were similar between the two groups (Table 1).

Transplants for Cholangiocarcinoma by Year

Over this 21-year time period, there were a varying number of transplants performed annually for a diagnosis of hilar CCA. Figure 2 reflects the initial interest in performing OLT for CCA, with approximately 10–20 transplantations per year between 1987 and 1990. Over the following decade in the 1990s, there was a significant decrease in the number of transplants, likely related to poor initial outcomes. During this time period there were less than ten transplants per year. Beginning in 2001, shortly after the initial results of the Mayo protocol were published in May 2000, there was a resurgence in the number of annual transplants being performed for CCA.

Fig. 2
figure 2

Liver transplants performed for cholangiocarcinoma (CCA) (October 1987 to May 2008)

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Survival and Prognostic Factors

The median post-transplant follow-up time for all 359 patients who underwent OLT for hilar CCA was 2.0 years (range 0.2–20.9 years). Overall survival of patients is depicted in Fig. 3. For all 359 patients who underwent OLT for a diagnosis of hilar CCA, the median post-transplant survival was 5.4 years (range 0.2–20.9 years), with 1-, 3-, and 5-year survival rates of 85.8, 63.5, and 51.4 %, respectively. A total of 14 (3.9 %) patients were lost to follow-up.

Fig. 3
figure 3

Overall survival post-OLT for 359 patients undergoing transplantation for cholangiocarcinoma (CCA) between 1987 and 2008. Overall 5-year survival was 51.4 % and median survival 5.4 years

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On univariate analysis, significant predictors of post-transplant survival were pre-transplant bilirubin levels (p = 0.01), incidental tumor found at the time of transplant (p < 0.01), transplant before the year 2000 (p < 0.01), graft rejection (p < 0.01), and use of standard immunosuppression (p < 0.01). Other variables that were included in the analysis but were not statistically significant included age, race, gender, candidate body mass index, MELD exception, Child-Turcotte-Pugh score, donor death mechanism, cold ischemia time, history of chronic liver disease, type of transplant (cadaveric vs. living-donor), and pre-transplant candidate albumin, INR, and creatinine (p > 0.05 for all these variables). There was no difference in survival between transplant regions (p = 0.40). On multivariate analysis, significant prognostic factors for worse post-OLT survival included undergoing liver transplantation before May 2000 (HR 11.25, 95 % CI 1.28–98.7) and having acute cellular rejection (HR 5.64, 95 % CI 1.14–27.8; Table 2).

Table 2 Prognostic factors for post-OLT survival for cholangiocarcinoma (CCA)
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The use of neoadjuvant chemoradiation has been shown to be associated with improved post-transplant outcomes for patients with CCA; however, these data are unfortunately not available in the SRTR database [18]. We performed a subset analysis on patients who received MELD exception points, as these were potentially the patients who received neoadjuvant therapy. Patients who received MELD exception points had 1- and 3-year survival rates of 89 and 74 %, respectively, compared to 82 and 56 % for those without MELD exception points (p = 0.01).

Prior to publication of the Mayo results in May 2000, the median survival was 3.3 years (range 0.2–20.9 years), compared to 7.8 years (range 0.03–8.2 years) after May 2000 (p < 0.01). Prior to May 2000, the 1-, 3-, and 5-year probabilities of survival were 82.0, 52.0, and 43.6 % respectively. After May 2000, the 1-, 3-, and 5-year probabilities of survival were 88.6, 74.2, and 58.7 % respectively (Fig. 4).

Fig. 4
figure 4

Comparison of post-transplant survival pre- and post-2000. There were 150 transplants before publication of the Mayo protocol results, and 209 transplants performed after publication in 2000. One-year survival was 82.0 and 88.6 %, respectively. Three-year survival was 52 and 74.2 %, and 5-year survival was 43.6 and 58.7 %, respectively (p < 0.01)

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Discussion

The introduction of the Mayo protocol in 2000 demonstrated that good long-term survival was possible with liver transplantation for CCA. As the interest in liver transplantation for CCA is growing in other centers, it is increasingly important to know if these outcomes are generalizable. Our study intended to determine if the results by the Mayo clinic are being replicated in other centers. Although we found that patients who underwent liver transplantation after publication of the Mayo protocol results had significantly better survival than those transplanted earlier, with 5-year survival rates improving from 44 to 59 % (p < 0.01), this is lower than the 5-year survival rate reported by the Mayo clinic of 73 %. This difference in survival is potentially due to our study accounting for multi-center data and variability in the pre-transplant protocol utilized at each center.

While this improved survival is likely due largely to the implementation of the Mayo Clinic protocol, patient selection likely also has an impact on improving survival. Our results show that the group of patients transplanted after 2000 were slightly older in age, more likely to be male, and beginning in 2003 they qualified for MELD exception points, thus decreasing the waitlist times for these patients prior to receiving a donor organ. Other factors that may have improved outcomes over time include improved tumor staging accuracy based on advances in radiographic and endoscopic tools, advances in surgical technique and other peri-operative factors. Our analysis also shows that worse outcomes were associated with a history of graft rejection. It is unclear, however, if this is due to the malignancy itself or if this is secondary to other transplant-related factors. Improvements in immunosuppressive regimens and standardization over time of post-transplant regimens may be in part responsible for improved outcomes.

There have been two prior registry-based studies that have reported post-OLT outcomes for patients with CCA. In a study using the Cincinnati Transplant Registry, the 5-year post-transplant survival was 23 % among 207 CCA patients transplanted worldwide between 1968 and 1997. Notably, this study showed that 51 % of patients had disease recurrence after transplantation, with a median time to recurrence of 9.7 months. The primary factors associated with tumor recurrence and mortality included positive surgical margins and advanced tumor stage [19]. Another study by Becker and colleagues using the UNOS/OPTN patient database reported on outcomes of 280 recipients of liver transplants for CCA between 1987 and 2005. Their results included an overall 1- and 5-year patient survival of 74 and 38 %, respectively. In this study, significant predictors of decreased survival included incidental diagnosis of CCA at the time of transplant as well as transplantation prior to 1994 [20]. On multivariate analysis our study did not find the incidental diagnosis of CCA to be an independent predictor of survival. One explanation is that these patients likely had underlying chronic liver disease and thus likely were diagnosed with early-stage CCA. In our study, the number of patients with an incidental diagnosis of CCA was lower than that in the Becker study. In our study the date of transplantation relative to the initial publication of the Mayo protocol results and a history of graft rejection were significant predictors.

There is no center-specific data available in this database, and therefore we could not determine which transplants were performed at the Mayo Clinic versus other centers. However, our analysis by region shows that there was no significant difference in survival by region.

Although our data suggest that post-transplant survival for CCA is improving after publication of the Mayo protocol, resection still plays a central role in the management of CCA. Surgical resection has comparable 5-year survival rates to OLT and should be regarded as the treatment of choice in patients who are deemed good resection candidates [6–8].

Our study has a number of limitations based on the information recorded by the SRTR. First, our study only establishes an association between publication of the Mayo protocol and improved post-transplant outcomes. Given the retrospective nature, we are unable to comment on causality. Furthermore, the SRTR database does not include tumor data such as specific modalities used to diagnose CCA, staging information including lymph node status, or specific details regarding pre-transplant therapy to confirm which neoadjuvant chemoradiotherapy protocol was implemented. Our analysis was also limited by the presence of missing data and unmeasured confounders. For example, we were also unable to determine impact of other possible prognostic variables such as history of cholecystectomy, CA 19-9 levels, waiting time, and histologic features from the explant. Several of these factors were previously shown in a study by the Mayo clinic to be significant predictors of tumor recurrence [21]. Similarly, the incidence of acute rejection in our study is lower than those previously reported, which may be related to underreporting and subsequent missing data. Furthermore, details regarding some data from SRTR are unfortunately not available, such as the differences between standard and non-standard immunosuppression. Finally, we were unable to quantify rates of tumor recurrence and its role in post-transplant survival. Our study’s strengths include the nationwide data with a large sample size and many variables to evaluate for predictors of long-term survival.

In conclusion, our nationwide database study shows that for selected patients with hilar CCA, liver transplantation can have a favorable outcome. Over time, graft survival rates have improved, with an overall 5-year survival rate of 51.4 % for all patients transplanted between 1987 and 2008. Moreover, survival has significantly improved since the Mayo protocol was published, with a 5-year survival rate of 58.7 % since 2000. This data suggests that highly selected patients with unresectable early stage hilar CCA may benefit from OLT, with notably improved outcomes and renewed interest in OLT over the past decade.