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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

We have previously reported excellent outcomes with liver transplantation for selected patients with early-stage perihilar cholangiocarcinoma (CCA) following neoadjuvant chemoradiotherapy. Our aim was to identify predictors of dropout before transplantation and predictors of cancer recurrence after transplantation. We reviewed all patients with unresectable perihilar CCA treated with neoadjuvant chemoradiation in anticipation for transplantation between 1993 and 2010. Predictors were identified by univariate and multivariate Cox regression analysis of clinical variables. In total, 199 patients were enrolled, of whom 62 dropped out and 131 underwent transplantation at our institution, with six undergoing transplantation elsewhere. Predictors of dropout were carbohydrate antigen 19-9 (CA 19-9) ≥ 500 U/mL (hazard ratio [HR] 2.3; P = 0.04), mass ≥ 3 cm (HR 2.1; P = 0.05), malignant brushing or biopsy (HR 3.6; P = 0.001), and Model for End-Stage Liver Disease (MELD) score ≥ 20 (HR 3.5; P = 0.02). Posttransplant, recurrence-free 5-year survival was 68%. Predictors of recurrence were elevated CA 19-9 (HR 1.8; P = 0.01), portal vein encasement (HR 3.3; P = 0.007), and residual tumor on explant (HR 9.8; P < 0.001). Primary sclerosing cholangitis (PSC), age, history of cholecystectomy, and waiting time were not independent predictors. Conclusion: Outcome following neoadjuvant chemoradiation and liver transplantation for perihilar CCA is excellent. Risk of dropout is related to patient and tumor characteristics and this can be used to guide patient counseling before enrollment. Recurrence risk is mostly associated with presence of residual cancer on explant. Patients with PSC do not have an independent survival advantage over de novo patients, but present with more favorable tumor characteristics. (HEPATOLOGY 2012;56:972–981)

Perihilar cholangiocarcinoma (CCA) constitutes approximately two-thirds of all cholangiocarcinomas and is the second most common primary liver cancer, with an annual incidence of approximately 1.2 in 100,000.1 Known risk factors in the western world include primary sclerosing cholangitis (PSC), with a lifetime risk of 5%-15%, and, much less frequently, choledochal cysts, Caroli syndrome, and cirrhosis of any cause.2

The clinical challenges of CCA are two-fold. First, the diagnosis is difficult to establish. The location is difficult to access and the tumor is highly desmoplastic, with a tropism for bile, leading to initial growth along the bile duct rather than into the parenchyma, making it hard to visualize by cross-sectional imaging. The desmoplastic nature of the tumor also results in paucicellular cytologic specimens, rendering a confident diagnosis of malignancy challenging. Intraluminal brushing or biopsy of a dominant stricture on endoscopic retrograde cholangiopancreaticography (ERCP), polysomy on fluorescence in situ hybridization (FISH), elevated tumor marker carbohydrate antigen 19-9 (CA 19-9), and visualization of a mass on imaging lead to a sensitivity of only 45%-50%, although a specificity of 96%-100%.3

Second, curative options are limited. Resection is the standard and may provide long-term survival, although many patients present with unresectable disease. After resection, 5-year survival rates generally range from 20%-30% (up to 40%-50% with R0 margins), with regional metastasis limiting long-term survival.4-8 Although liver transplantation alone was a dismal failure for patients with perihilar CCA,9, 10 when used in combination with neoadjuvant chemoradiotherapy it has evolved into a promising option for unresectable cases. Encouraged by results from our small series in which 22% 5-year survival was achieved by chemoradiation alone11 and that of the University of Nebraska using neoadjuvant high-dose brachytherapy and chemotherapy before transplantation,12 in 1993 we developed a protocol combining neoadjuvant external beam radiotherapy (EBRT), brachytherapy, chemotherapy, and liver transplantation. Subsequent reports have shown excellent results, with 5-year recurrence-free survival rates of approximately 70%.13-16

Although liver transplantation appears beneficial in those who complete the protocol, there is a group of patients who do not make it to transplantation (dropout) due to cancer progression or complications of the treatment. To date, predictive markers of dropout are unknown, which limits our ability to counsel patients. We have reported recurrence of cholangiocarcinoma following transplantation in 17%.15 In our earlier experience with 65 transplanted patients, we found increased age, elevated CA 19-9, prior cholecystectomy, mass on imaging, and residual tumor in explant with perineural invasion to be associated with recurrence. However, small sample size precluded multivariate analyses and hence identification of statistically independent predictors of recurrence. Additionally, no analysis of wait-list dropout was performed in the earlier analysis. Because of the shortage of liver allografts as well as the morbidity of neoadjuvant therapy and transplantation, we feel it is essential to identify who will most benefit. Thus, the aim of the present study was to identify independent predictors of dropout before transplantation, as well as predictors of cancer recurrence after transplantation.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

Study Design.

Since January 1993, all patients with unresectable perihilar cholangiocarcinoma presenting to our institution were considered for a treatment protocol consisting of neoadjuvant chemoradiation followed by liver transplantation as described.17-19 All patients were evaluated by an experienced hepatobiliary surgeon and determined unresectable in the setting of bilobar involvement of major perihilar structures or underlying PSC, the latter due to the presence of underlying parenchymal disease and/or possible multifocal disease. All patients treated in accord with this protocol between 1/1993 and 10/2010 were prospectively followed through 12/2010.

Diagnosis was established in the presence of (1) positive or strongly suspicious intraluminal brush or biopsy, or (2) a radiographic malignant-appearing stricture plus either CA 19-9 > 100 U/mL in the absence of acute bacterial cholangitis, polysomy on FISH (available since 2003), or well-defined mass on cross-sectional imaging. Patients were excluded if they had any evidence of extrahepatic disease or regional lymph node involvement, a previous malignancy (excluding skin or cervical cancer) 5 years before, prior abdominal radiotherapy, uncontrolled infection, previous attempt at surgical resection with violation of the tumor plane, or any medical condition precluding transplantation. Notably, vascular encasement and stricture/mass extension along the duct were not contraindications, although a mass with a clear radial diameter of >3 cm was excluded. Patients with longitudinal tumor extension along the bile duct were included, and thus, lesions reported to be larger than 3 cm in the data set represented longitudinal extension.

Patients received neoadjuvant therapy according to our published protocol.17-19 EBRT was administered to a total dose of 4500 cGy in 30 fractions of 150 cGy twice daily for 3 weeks. The radiosensitizing chemotherapy regimen has changed over time from daily bolus fluorouracil (5-FU) at 500 mg/m2 for the first 3 days to continuous infusion of 5-FU given for the duration of EBRT. A transluminal radiation boost is then delivered through transcatheter Iridium-192 seeds placed under fluoroscopy guidance. The delivery has changed from giving 2000 cGy over 24 hours using low-dose-rate brachytherapy, to, most recently, high-dose brachytherapy of either 1200-1600 cGy in two to four fractions. Whenever brachytherapy was technically not possible, an extra boost of EBRT (1000-1500 cGy) was given. Patients then began chemotherapy consisting of oral capecitabine at 2000 mg/m2 in two divided doses for 2 out of every 3 weeks until transplantation. An open staging laparotomy (since 2004, a hand-assisted laparoscopy) with routine biopsy of hepatic artery and pericholedochal lymph nodes plus any suspicious lesion was performed. Timing of staging has varied with differences in allocation system over time, although since 2007, staging has been performed as time for transplantation nears. Only those with a negative staging operation, or no evidence of disease metastasis, remain eligible for transplation.

Transplantation techniques have been described extensively.13 Both deceased- and living-donor transplants were performed. Before institution of the Model for End-stage Liver Disease (MELD) allocation system in 2002, no additional priority for organ allocation beyond wait time and medical status was granted. After the MELD system was introduced, patients received additional priority for deceased-donor liver allocation per a regional agreement that allowed an initial MELD score of 22. Similar to what is allowed for hepatocellular carcinoma, the score was adjusted to a 10% increase in predicted wait list mortality at a set interval, except that this interval increase was every 6 months instead of every 3 months. The distal bile duct margin was sent for frozen section and if positive for tumor, pancreaticoduodenectomy was performed. Patients received standard immunosuppression (currently short-term mycophenolate mofetil and prednisone taper with tacrolimus monotherapy). Posttransplant follow-up was performed at our institution and included CA 19-9 with each visit, and abdominal computed tomography (CT) scan (discontinued after 5 years). After the initial transplant episode, patients were seen at 4 months, 12 months, and annually thereafter. This study was approved by the Mayo Clinic Rochester Institutional Review Board.

Data Collection.

Data were prospectively collected since initiation of this protocol. A mass was defined as a well-defined lesion on either magnetic resonance imaging (MRI) or CT. Perihilar thickening or enhancement was not considered a mass. Mass size was defined as the diameter measured radially or longitudinally, whichever was largest. The MELD value represents the calculated MELD.20

Outcome Definition and Statistical Analyses.

Dropout is defined as positive staging, tumor metastasis, death, or withdrawal because of intolerable side effects before transplantation. Recurrence is defined as radiographic or pathologically confirmed evidence of cholangiocarcinoma after transplantation. Continuous variables were expressed as median (range) of their natural or logarithmic scale, and categorical variables were expressed as n (% of total).

Statistical analyses included univariate and multivariate Cox regression analyses of baseline predictors for time to dropout or recurrence (Pin = 0.05 and Pout = 0.10). For the prediction of dropout, T0 was set at time of presentation to our transplant clinic. For the prediction of recurrence, two models were created: one with T0 at presentation (baseline predictors) and one with T0 at transplant (transplant predictors). Survival was calculated using Kaplan-Meier analysis and compared by log-rank testing. Comparison between subgroups was based on Chi-square (categorical) or Mann-Whitney U testing (continuous variables). Statistical significance was set at P < 0.05. All analyses were performed in SPSS (version 16.0, Chicago, IL).

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

Total Population.

A total of 199 patients were enrolled. Median age was 51 years (range 19-70), 144 (72%) patients were male, and 127 (64%) had underlying PSC. There were 36 (28%) PSC patients who presented with CCA as their first manifestation. There were 127 patients with biliary stents in place (endoscopic= 97, percutaneous =30) at the time of diagnosis. Table 1 summarizes the diagnostic criteria. There were 103 (52%) patients with definite pathological confirmation. Of those 96 who met other criteria but did not have an initial tissue diagnosis, over half (55%) either dropped out before transplant from disease metastasis (n = 22), had evidence of residual tumor on explant (n = 30), and/or developed recurrent cancer (n = 14). Median follow-up was 2.6 years (range 0.11-17.8 years). Overall (intent-to-treat) survival is presented in Fig. 1A.

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Figure 1. Flow of patients from start of neoadjuvant treatment to transplantation from January 1993 to October 2010. A total of 62 patients dropped out, and 137 underwent transplantation either at our institution (n = 131) or elsewhere (n = 6).

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Table 1. Diagnostic Criteria for All Eligible Patients With Perihilar Cholangiocarcinoma (PSC) Who Were Enrolled and Underwent Neoadjuvant Therapy in Anticipation of Transplantation (n = 199) in Association With Their Underlying Etiology and Outcomes*
Diagnostic CriteriaNo.PSC (n = 127) versus De Novo (n = 72)Dropout (n = 62)Tumor on Explant (n = 61)Recurrence (n = 26)
  • *

    All results are expressed in absolute numbers (n).

Definite evidence of malignancy on intraluminal brushing or biopsy (i.e., positive for adenocarcinoma)103PSC7126185
De novo3214137
Stricture + combination of two or more of CA 19-9 > 100, mass, suspicious brushing or biopsy, and/or polysomy69PSC417114
De novo2810124
Stricture + CA 19-9 > 1006PSC3111
De novo3021
Stricture + mass5PSC0000
De novo5222
Stricture + polysomy5PSC5000
Stricture + suspicious brushing1PSC1100
Stricture + weight loss + obstructive jaundice5PSC1000
De novo4101
Diffuse strictures + CA 19-9 > 100 + mass1PSC1011
Diffuse strictures + suspicious brushing + polysomy1PSC1010
Intraductal polypoid lesion on ERCP + polysomy1PSC1000
Diffuse strictures + suspicious brushing + trisomy (repeatedly)1PSC1000
Diffuse strictures + polysomy1PSC1000

Dropout Before Transplantation.

As summarized in Fig. 2, a total of 62 patients (31%) dropped out after a median of 4.7 months (range 1.1-17.1 months). Fifty-five patients had cancer progression, of whom 19 were diagnosed before and 36 at the time of staging with metastatic disease found in regional lymph nodes (n = 14) or intrahepatic (n = 6) or extrahepatic lesions (n = 16). Of these, 45 (82%) died from cancer progression, and the remaining 10 left our institution immediately after dropout and were lost to follow-up. One patient was no longer a transplant candidate because of progressive clinical deterioration, and she died from liver failure. Five patients died from cardiovascular arrest (n = 2), sepsis (n = 1), liver failure (n = 1), or gastrointestinal bleeding (n = 1) without evidence for cancer progression. Total mortality in the patients who dropped out was thus 83% (n = 52), and death occurred after a median of 3.6 months from detection of metastasis (range 0-22.1 months with one patient surviving up to 96.7 months after detection of metastatic disease on staging). There were no differences (including waiting time) between patients (n = 6) who dropped out after initial negative staging compared with those who did so before staging (n = 20), or those who underwent transplant (n = 131; data not shown).

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Figure 2. (A) Overall Kaplan-Meier survival curve in all patients enrolled in our protocol (n = 199) from presentation to death (n = 90). Patients are censored at last follow-up if alive regardless of treatment received (intent to treat). (B) Kaplan-Meier survival after transplantation in all patients (n = 131; n = 36 deaths). Patients are censored at last follow-up if alive. (C) Recurrence-free Kaplan-Meier survival in all patients (n = 131) from transplantation to cholangiocarcinoma recurrence or death (n = 38 recurrence or death). Patients are censored at last follow-up if alive and without recurrence.

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The results of the univariate and multivariate analyses of waiting list dropout are presented in Table 2. Presentation with painless jaundice or weight loss, visible tumor mass on cross-sectional imaging (especially with largest diameter ≥ 3 cm), positive or suspicious intraluminal brushing or biopsy, elevated CA 19-9, vascular encasement, and higher MELD score were all significant predictors of dropout in the univariate analysis. Interestingly, underlying PSC, age, history of cholecystectomy, or use of percutaneous biliary drainage was not predictive. The final multivariate model identified the following independent predictors: mass size ≥ 3 cm, positive or suspicious intraluminal brushing or biopsy, elevated CA 19-9, and higher MELD score.

Table 2. Univariate and Multivariate Cox Models of Baseline Characteristics for Patients Who Dropped Out From the Protocol (n = 62) Versus Those Who Remained Eligible for Transplant (Defined as “Success,” n = 137)*
 UnivariateMultivariate
Baseline CharacteristicsDropout (n = 62Success (n = 137)Hazard Ratio95% CIPHazard Ratio95% CIP
  • *

    Categorical variables are expressed in n (%) of the outcome and continuous variables as median (range). For abbreviations, see first page footnote.

  • Patients without a visible mass on cross-sectional imaging are assumed to fall in mass size category 0-2.9 cm.

  • Given the wide distribution of tumor marker CA 19-9, a logarithmic conversion is used for the continuous variable. Each log changes signifies a change of 101 (e.g., from 10 to 100, or 100 to 1000). Median CA 19-9 values were 221 (range 1-13,200) and 51.3 U/mL (range 0-28,750) for the dropout and success groups, respectively.

Age52.2 (27-70)50.6 (19-67)1.010.99-1.040.38
PSC35 (56)92 (67)0.740.43-1.170.17
Inflammatory bowel disease31 (50)76 (55)0.860.52-1.410.54
PTC drain versus ERCP stent10 (16) 33 (53)20 (15) 64 (48)1.020.50-2.070.96
Cholecystectomy10 (16)33 (24)0.740.38-1.470.39
Onset of symptoms (days)81 (31-707)103 (22-866)1.001.00-1.000.67
Painless jaundice47 (76)76 (55)2.071.16-3.710.01
Weight loss42 (68)76 (55)1.690.99-2.890.05
Opioid use for abdominal pain4 (6)6 (4)1.640.60-4.540.34
Mass seen on imaging43 (69)68 (50)2.241.30-3.850.004
Mass largest diameter (cm)3.0 (0.9-5.0)2.5 (0.6-4.5)1.611.18-2.200.003
Mass size    <0.001  0.05
 0-2.9 cm (ref)43 (69)121 (88)    
 3 cm5 (8)5 (36)2.761.09-7.012.270.79-6.50
 >3 cm11 (18)14 (10)3.201.74-5.892.141.08-4.24
Positive/suspicious brushing or biopsy49 (79)91 (66)2.281.15-4.500.023.631.67-7.89.001
Polysomy on FISH15 (24)40 (29)1.260.59-2.700.56
CA 19-9 (log)2.34 (0-4.12)1.77 (0-4.46)1.681.27-2.25<0.001
CA 19-9 (U/mL)    0.002  .04
 <100 (ref)24 (39)83 (61)    
 100-49915 (24)34 (25)1.670.87-3.181.550.78-3.08
 ≥50023 (53)18 (13)2.851.60-5.062.291.22-4.32
MELD score12 (6-26)10 (6-35)1.061.02-1.100.007
MELD score    0.02  .02
 <1022 (35)73 (53)    
 10-2030 (48)55 (41)1.931.10-3.351.350.73-2.49
 ≥209 (15)9 (7)2.701.24-5.883.481.46-8.27
Vascular encasement31 (50)44 (32)1.821.10-2.990.02
Atrophy/hypertrophy complex20 (32)42 (31)0.950.56-1.630.86

Transplantation.

A total of 131 patients (66%) underwent liver transplantation at our institution after a median wait time of 6.9 months (range 1.97-34.3 months) with a deceased donor in 88 (67%), a living donor in 42 (32%), and a familial amyloidosis donor in one patient. Median calculated MELD was 11 (range 6-40), and median CA 19-9 was 55 U/mL (range 0-2370). On explant, residual tumor was found in 61 patients (47%) of whom 24 had perineural and three regional lymphovascular invasion. Histological grade was G1 (well differentiated; n = 1), G2 (moderately differentiated; n = 22), G3 (poorly differentiated; n = 29), and G4 (undifferentiated; n = 4). In five patients, grading could not be performed because of radiation effects.

Eleven patients required retransplantation (8%) after a median of 1.2 months (range 0.03-163.6) for primary nonfunction (n = 3), hepatic artery thrombosis (n = 6), ischemic cholangiopathy (n = 1), and recurrent PSC (n = 1). In total, 36 patients died (27%), because of cancer recurrence (n = 24), multiorgan failure (n = 3), invasive intracranial aspergillosis (n = 1), graft-versus-host disease (n = 1), massive pulmonary embolism (n = 1), sepsis (n = 1), subdural hematoma (n = 1), pulmonary infection (n = 1), intraoperative intra-abdominal hemorrhage (n = 1), and posttransplant lymphoproliferative disease (PTLD; n = 1). One patient died in an outside institution from an unknown cause with no evidence of recurrence at 6.7 months of follow-up. Posttransplant 1-, 2-, and 5-year survival was 91% (95% CI 86-96), 85% (95% CI 79-91), and 71% (95% CI 62%-80%), respectively (Fig. 1B).

Recurrence After Transplantation.

A total of 26 patients (20%) developed cancer recurrence at a median of 23 months (range 1-128) after transplantation. There were 17 with distant and nine with locoregional metastases. Median survival after recurrence was 6.9 months (range 0-40). All but two patients (alive at 1 and 10 months at end of follow-up) died after recurrence. Recurrence-free 1-, 2-, and 5-year survival was 87% (95% CI 82-93), 80% (95% CI 72-87), and 68% (95% CI 59-77), respectively (Fig. 1C).

Table 3 summarizes predictors of recurrence. Of the variables available at enrollment, age, mass, CA 19-9, and vascular encasement were significantly associated with risk of recurrence. Also, patients with PSC-related CCA had a lower risk of recurrence than those with de novo CCA. In the multivariate model, however, only elevated CA 19-9 at presentation and complete portal vein encasement remained independent baseline predictors of recurrence after transplant.

Table 3. Univariate and Multivariate Cox Models of Characteristics at Presentation and at Time of Transplantation for Transplanted Patients Who Developed Recurrence (n = 26) Versus Those Who Remained Free of Recurrence (n = 105) at Our Institution*
 UnivariateMultivariate
 Recurrence (n = 26)Free of Recurrence (n = 105)Hazard Ratio95% CIPHazard Ratio95% CIP
  • *

    Categorical variables are expressed in n (%) and continuous variables as median (range). For abbreviations, see first page footnote.

  • Given the wide distribution of tumor marker CA 19-9, a logarithmic conversion is used. Each log changes signifies a change of 101 (e.g., from 10 to 100, or 100 to 1000). At presentation, actual median CA 19-9 values were 112 (range 0-28,750) and 45.8 U/mL (0-26,200) for the recurrence and no-recurrence groups, respectively. At transplant, median CA 19-9 values were 132 (range 0-2370) and 47.3 U/mL (range 0-1701) for the recurrence and no-recurrence groups, respectively.

  • Extended criteria donor included age > 65 (n = 14), death after cardiac death (n = 6), >20% macrosteatosis (n = 3), and high-risk donor (n = 2).

Baseline characteristics
 Age53 (36-67)50 (22-66)1.061.01-1.100.01
 PSC11 (42)76 (72)0.350.16-0.770.009
 PTC drain versus8 (31)12 (11)0.610.26-0.26
ERCP stent14 (54)47 (45)1.45
 Cholecystectomy9 (35)24 (23)1.490.66-3.340.34
 Onset of symptoms (days)104 (51-274)111 (22-866)1.000.99-1.000.41
 Mass seen on imaging18 (69)48 (46)3.661.56-8.590.003
 Mass largest diameter (cm)2.5 (2.0-4.0)2.4 (0.6-4.5)1.790.89-3.590.10
  Mass ≥ 3 cm6 (23)10 (9)3.971.53-10.350.005
 Positive/suspicious brushing or biopsy17 (65)71 (68)1.070.47-2.410.87
 CA 19-9 (log)2.05 (0.48-4.46)1.70 (0-4.42)1.851.24-2.780.0031.791.14-2.800.011
 CA 19-9 (U/mL)  0.12  
 <100 (ref)13 (50)65 (62)      
 100-4996 (23)27 (26)      
 ≥5007 (27)11 (10)    1.570.59-4.17
 MELD score10 (6-25)10 (6-35)2.611.04-6.540.96
 Vascular encasement12 (46)30 (29)2.251.03-4.880.04
 Complete portal vein encasement8 (31)11 (11)4.191.78-9.870.0013.301.38-7.860.007
Transplant characteristics
 Time on wait list until  transplantation (days)200 (65-423)211 (60-1044)1.001.00-1.000.19
 Wait list time ≥1 year2 (8)29 (28)0.250.06-1.080.06
 Living donor versus7 (27)36 (34)0.970.41-2.330.95
deceased donor (ref)19 (73)69 (66)
 Extended criteria3 (12)22 (21)0.790.23-2.630.70
donor versus standard (ref)23 (88)83 (79)
 Pancreaticoduodenectomy4 (15)8 (31)1.850.64-5.370.26
 Cell Saver-derived autologous  blood transfusion11 (42)39 (37)1.640.75-3.600.22
 CA 19-9 (log)2.15 (0.95-3.37)1.73 (0.48-3.23)2.331.14-4.750.02
 MELD10 (6-23)12 (6-41)0.980.92-1.040.51
 Residual tumor tissue on explant23 (88)38 (36)9.832.95-32.76< 0.0019.832.95-32.76< 0.001
 Perineural invasion11 (42)13 (12)4.051.86-8.83< 0.001   

Of variables available at the time of transplant, CA 19-9, residual tumor on the explant, and perineural invasion were significantly associated with increased recurrence risk in univariate analyses. Donor factors that have been associated with recurrence of hepatocellular carcinoma were analyzed, including living donor versus deceased donor, donor age, and cold ischemia time and were found to be not significant. Additionally, transfusion of both autologous blood and packed blood cells were analyzed and found to be not predictive of recurrence. Interestingly, wait list time was not significantly associated with recurrence, even after stratification for MELD era or living versus deceased donors (data not shown). In the multivariate model, the most significant predictor of recurrence was residual tumor on explant with an HR of 9.83 (P < 0.001).

It is important to note, however, that 38 of 61 patients with residual cells (62%) did not develop recurrence. We found no significant differences in clinical characteristics (including waiting time and follow-up time) between patients who did or did not develop recurrence, indicating there may be as yet unknown factors such as inherent tumor biology, which may determine responsiveness to treatment and recurrence.

Subgroup Analyses.

Two subgroup analyses were performed to examine the robustness of our results. First, we compared patients who had PSC-related CCA with those who had de novo CCA to explain why, univariately, PSC patients appear to do better but in multivariate models this effect disappears. We found that this is likely due to patients with PSC having a more favorable profile with younger age (median 48 versus 55 years; P < 0.001), less mass formation (47% versus 72%; P = 0.001), less vascular encasement (26% versus 58%; P < 0.001), lower CA 19-9 levels (median 51 versus 150 U/mL; P = 0.001), less painless jaundice (51% versus 81%; P < 0.001), and less weight loss (53% versus 71%; P = 0.02). In a sensitivity analysis (repeating the univariate Cox analyses of dropout for each subset separately), PSC patients had the same significant predictors as the overall population (data not shown). For de novo patients, the same held true, although the differences were nonsignificant, given the smaller number of patients and lower statistical power, for all variables except mass size ≥ 3 cm (22% in dropout versus 27% in success group; HR 1.07; P = 0.89) and MELD score (median 10.6 versus 11.0, respectively; HR 0.99; P = 0.79).

Second, although the majority of patients (n = 183; 92%) eventually had definite proof of CCA by either pretransplant intraluminal brushing or biopsy, radiological evidence of a well-defined tumor mass, tumor tissue on explant, or CCA recurrence, 16 patients (8%) did not, even though they had constitutional symptoms, a malignant stricture, CA 19-9 > 100 U/mL, and/or positive FISH. A sensitivity analysis showed that removal of these patients did not alter survival (Fig. 3) or the results of the univariate and multivariate models (data not shown).

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Figure 3. Kaplan-Meier recurrence-free survival curve when patients with no mass on diagnostic imaging, negative brushing or biopsy, no residual tumor, and no tumor recurrence (n = 16) are excluded (dotted line; n = 115; n = 38 recurrence or death) compared with the total population (solid line, same as Fig. 1C). Comparison based on log-rank testing.

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Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References

Since 1993, we have offered a protocol combining the known benefits of neoadjuvant chemoradiotherapy with liver transplantation in an attempt to develop an effective therapy for patients with unresectable perihilar cholangiocarcinoma. With this protocol, our current posttransplant survival of 91%, 85%, and 71% at 1, 2, and 5 years, respectively, is similar to that achieved for other standard indications for orthotopic liver transplantation such as hepatocellular carcinoma or hepatitis C virus infection. Despite the aggressive pretransplant treatment, however, 26 patients (20%) developed disease recurrence. Additionally, 62 patients (31%) had disease progression or other issues precluding transplantation.

This study identifies those factors important in predicting risk for dropout as well as recurrence, which is particularly useful given the marked allograft shortage as well as the considerable toxicity of the treatment,. We found that a mass of ≥ 3 cm, CA 19-9 levels > 500 U/mL, positive or suspicious results on intraluminal brushing or biopsy, and MELD score > 20 predicted an increased risk of dropout before transplantation. Factors that predicted recurrent CCA included elevated CA 19-9, portal vein encasement, and presence of residual tumor on explant pathology.

The predictors of dropout are biologically plausible. A mass size ≥ 3 cm was associated with a two-fold increased risk. Growth may represent a greater opportunity to metastasize or more aggressive tumor biology, particularly because mass formation is not a typical early feature of CCA.21 It is important to note, however, that these measurements are subject to interpretation because of surrounding inflammation, which obscures borders and can makes determination of exact tumor size difficult. In addition, we believe extension along the bile ducts may not portend the same prognosis as radial growth into the parenchyma. We have generally excluded patients with a tumor > 3 cm in a radial diameter. An elevated CA 19-9 at enrollment, especially if over 500 U/mL, was also predictive of dropout. Although CA 19-9 can be elevated in numerous biliary conditions such as obstruction or cholangitis, in our study it was only recorded after resolution of these conditions. This finding could therefore represent overall tumor burden or biology and should heighten clinical awareness.

The presence of positive or suspicious cytology or pathology also likely represents a tumor that is more advanced. The yield of diagnostic sampling is therefore generally unsatisfying, as was also apparent in our patients. Importantly, however, 55% of those with an initial negative result developed overt tumor progression, disease recurrence, or definite tissue diagnosis at explant. The use of direct visualization and biopsy by means of cholangiopancreatoscopy (Spyscope) may eventually improve the diagnostic sensitivity of endoscopic biopsy, although thus far data are limited.22 Finally, a higher MELD score was associated with a 3.5-fold increased risk of dropout, which was mostly driven by elevations in bilirubin and international normalized ratio. A higher MELD score may thus represent greater tumor burden. However, it may also reflect more advanced underlying liver disease, which may make patients more prone to complications of therapy. Indeed, chemoradiation regimens are often interrupted and doses reduced in patients with hyperbilirubinemia.

For the prediction of recurrence in the posttransplant setting, CA 19-9 at enrollment again was significant, as was encasement of the portal vein. We are uncertain of the basis for the latter but suspect that it may also reflect tumor burden. The fact that vascular invasion was not predictive of recurrence confirms that this radiographic finding is due to tumor extension along the vein rather than invasion, unlike in hepatocellular carcinoma. Of all transplant-related variables, having residual tumor cells was the strongest predictor of recurrence, with a near 10-fold increased risk. Interestingly, however, the 62% with residual tumor who did not develop recurrence were not different from those who did, based on known parameters. Unfortunately, we do not know whether there are inherent biological principles of the tumor that make it less radiosensitive or more prone to early dissemination, or whether some tumors simply cannot be completely eradicated by the chemoradiotherapy. Further research in this field is desperately needed. Although finding residual cancer in the explant is an anxiety-provoking event, there is currently no proven benefit for adjuvant therapy.

The predictors of recurrence we found in our current study are not identical to those identified in our earlier experience.15 In the current analysis we did not find age or history of cholecystectomy to be significant, though these were previously identified predictors of recurrence. Part of the discrepancy lies in the substantial difference in sample size; in our earlier study, 65 patients were included with only 11 events, versus 131 and 26 now, and the earlier results were only based on univariate analyses. In the present study, waiting time was not associated with risk of recurrence, even after correction for MELD era or living versus deceased donation. Although outliers existed, the overall spread in waiting time for those who made it to transplant may be too homogeneous to demonstrate a difference. Furthermore, the actual key factor may be the response to neoadjuvant therapy, rather than time. Unfortunately, the lack of accessible tissue limits our ability to determine this serially, although certainly future advances in complex molecular analysis of these tumors may allow this question to be addressed.

It was notable that neither age nor PSC were significant in the multivariate analyses. Comparing patients with PSC-related CCA and de novo CCA taught us that PSC patients usually presented with more favorable tumor characteristics, potentially because they are monitored more closely or undergo a more rapid evaluation. Patients with PSC who present with more advanced disease do as poorly as de novo CCA patients. In our sensitivity analyses, we found the same factors to be predictive of dropout in the PSC group as in the total group. In contrast, in de novo patients, mass size, and MELD score did not seem to discriminate between those who dropped out versus those who proceeded to transplant. Although statistical power is low because of smaller numbers of patients, it may be that MELD score is less informative in patients with de novo CCA because of lack of parenchymal disease, resulting in lower scores with less variability. Lack of parenchymal disease in de novo patients may also lead to easier mass detection. This is suggested by the observation that 72% of these patients had a visible mass (compared with 47% in PSC) and a median size of 2.6 cm. Further research in this field is needed. At this point, however, mass size or higher MELD in patients with de novo CCA appear less predictive than in PSC.

Our results continue to demonstrate excellent outcomes following neoadjuvant therapy and liver transplantation for early-stage perihilar CCA, similar to earlier studies.14, 15, 18, 19 Indeed, our 71% 5-year posttransplant survival is similar to the 68% for all deceased liver transplants based on the latest Organ Procurement and Transplantation Network data. We believe this is achieved by a combination of rigorous selection criteria and the effectiveness of neoadjuvant radiation and chemotherapy to eliminate or at least contain the tumor while awaiting transplantation. In a recent series by Hong et al.,23 outcomes of patients transplanted with more advanced disease, including both intrahepatic (n = 26) and perihilar CCA (n = 14), were described. Based on variables that predicted higher recurrence risk (multifocality, perineural and lymphovascular invasion, infiltrative growth, PSC, perihilar CCA, and absence of neoadjuvant therapy.), patients were classified into three risk groups. Although the 5-year survival in the low-risk group (78%) mimics ours, it is important to note that only two of the 11 low-risk patients had perihilar CCA. The 5-year recurrence-free survival for the intermediate- and high-risk groups, which had the majority of the perihilar cancers, was very poor. Additionally, the proposed use of direct tumor biopsies before and after neoadjuvant treatment to obtain prognostic information is worrisome, as this has been associated with a higher risk for tumor dissemination.24 Although any attempt to optimize treatment options for patients with this devastating disease is highly encouraged, there are no curative options for those with advanced disease at this point.

Our study has limitations. First, although this is the largest series to date, overall numbers from a statistical standpoint are still small, especially for the analysis of recurrence risk. We therefore limited the list of potential predictors to only the most clinically relevant. Second, even though most patients are followed at our institution, we could not assess final outcome for 10 patients who left our clinic after dropout, who typically returned to their local centers for palliative care. Lastly, despite all our efforts to obtain a definite tissue diagnosis in patients whose clinical picture is highly compatible with CCA, we were unable to obtain definite evidence in 16 patients. However, we showed that excluding these patients did not significantly alter our results.

In conclusion, patients who undergo neoadjuvant chemoradiation followed by liver transplantation have excellent 5-year recurrence-free survival. Elevated CA 19-9, mass ≥ 3 cm, malignant brushing or biopsy, and higher MELD score were all associated with increased risk of dropout before transplantation. Elevated CA 19-9, encasement of the portal vein, and, most importantly, residual tumor cells were associated with increased risk for recurrence after transplantation. Ideally, novel therapies will become available in the future that could be offered to those patients identified as at higher risk of disease progression before transplantation or recurrence after transplantation.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. References
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