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Original Clinical Science—Liver

Neoadjuvant Chemoradiotherapy and Liver Transplantation for Unresectable Hilar Cholangiocarcinoma: The Irish Experience of the Mayo Protocol

Zaborowski, Alexandra MD1; Heneghan, Helen M. PhD1; Fiore, Barbara MD1; Stafford, Anthony MD1; Gallagher, Tom MD1; Geoghegan, Justin MD1; Maguire, Donal MD1; Hoti, Emir MD1

Author Information
doi: 10.1097/TP.0000000000003114
  • Free

Abstract

INTRODUCTION

Hilar cholangiocarcinoma (hCCA) is a rare malignancy with a poor prognosis. Although primary sclerosing cholangitis (PSC) is a well-documented risk factor, the majority of cases arise de novo without any identifiable cause.1,2 Complete excision remains the cornerstone of curative treatment and is considered standard of care for localized disease.3

Despite advances in surgical technique and perioperative management, surgery for hCCA continues to be highly complex and technically challenging, associated with significant major morbidity and mortality and relatively high R1 resection rates when compared with most elective cancer resections.4,5 A negative resection margin, the most important predictor of outcome, is only achieved in 60%–80% of cases and over 50% of patients who undergo surgery with curative intent develop disease recurrence.6 Disappointingly, long-term survival following radical resection remains low, ranging from 20% to 40% at 5 years.7

A major challenge in the management of hCCA is the late occurrence of disease-specific symptoms. As a result, <50% of patients have resectable disease at the time of diagnosis.8 Furthermore, damaged liver parenchyma and an abnormal biliary tree in the setting of PSC precludes resection in patients who develop hCCA. Over the past few decades, there has been considerable focus on defining the role of orthotopic liver transplantation (OLT) in the management of early unresectable hCCA. Initial experiences in the late 1980s were disappointing, with several centers reporting high recurrence rates and poor long-term survival. The Cincinnati Transplant Tumor Registry reported 28% five-year survival with a 51% tumor recurrence rate,9 while the Spanish liver transplant centers reported 30% three-year survival.10 As a result, unresectable hCCA became a contraindication to liver transplantation.

In the early 1990s, based on a concept proposed by the University of Nebraska, the Mayo Clinic developed a multimodal treatment approach consisting of neoadjuvant chemoradiotherapy (nCRT) followed by liver transplantation for highly select patients with early unresectable hCCA arising de novo (solitary tumors <3 cm, no evidence of lymph node involvement) or hCCA arising in the setting of PSC.11 Preliminary results were promising, demonstrating improved locoregional control and long-term survival with a 5-year survival of 82%.12,13 Subsequent outcome data have been encouraging, with overall 5-year recurrence free survival rates of ~65%–70% consistently reported.14-17 On the basis of these positive experiences, the United Network of Organ Sharing/Organ Procurement and Transplantation Network approved the allocation of a standard model of end-stage liver disease exception score for patients with hCCA who completed a standardized neoadjuvant treatment protocol.18

Despite these reports, concerns exist regarding the reproducibility of results and justification of the use of scarce liver grafts. In 2014, we published our initial experience of a consecutive series of patients with unresectable hCCA treated with nCRT followed by liver transplantation with curative intent.19 Herein, we present a current analysis of the Irish experience with this treatment protocol, including our long-term outcomes.

MATERIALS AND METHODS

Patient Population

Patients attending the National Liver Transplant Centre between October 2004 and December 2016 with unresectable hCCA, either de novo or arising in the setting of underlying PSC, and treated with curative intent involving nCRT followed by liver transplantation were prospectively studied. The study protocol was reviewed and approved by the institutional Research and Ethics Board. The treatment protocol was based on the previously published Mayo Protocol, including their inclusion and exclusion criteria, nCRT, and operative staging, either preoperatively or at the time of transplantation.12 Baseline demographic, clinical, staging, treatment, pathologic, and survival data were recorded in a prospectively maintained database.

Assessment

Diagnosis of hCCA was established by preoperative pathological (via endoluminal biopsy) or cytological (via biliary brushing) analysis or by the presence of a radiologically characteristic malignant stricture in combination with an elevated serum carbohydrate antigen 19-9 (CA 19-9) of >100 U/mL. Importantly, CA19-9 was measured in the absence of ascending cholangitis. Tissue specimens were reviewed by a specialist biliary pathologist. All patients were radiologically staged with a computed tomography of thorax, abdomen, and pelvis (CT-TAP). In the absence of metastatic disease, a staging laparoscopy or laparotomy was performed. Intraoperative ultrasonography was used to evaluate the liver, an excisional biopsy of a lymph node in the hepatic pedicle was performed and any additional suspicious lesions or lymph nodes were also biopsied. Peritoneal washings were obtained for cytological analysis if fluid was identified in the abdominal cavity. Exclusion criteria included a tumor mass with a radial diameter >3 cm on cross-sectional imaging, an open or transperitoneal biopsy of the tumor and a history of previous surgery or chemotherapy for hCCA. Encasement of the hepatic artery was not a contraindication to the treatment protocol. Patients were deemed unresectable on the basis of radiological appearances following formal discussion at our institutional multidisciplinary transplant meeting consisting of a minimum of 3 transplant surgeons, 3 hepatologists, and 2 radiologists.

Treatment Protocol

The neoadjuvant treatment protocol was standardized throughout the study period as previously described.19 Patients received a single 7.5 Gy dose of brachytherapy delivered by percutaneous transhepatic catheter, in addition to 45–55 Gy of external beam radiotherapy, delivered at a dose of 2 Gy per day, for 5 days per week. Target volumes were calculated using pretreatment computed tomography. The gross target volume included all radiologically visible tumor, the clinical target volume consisted of gross target volume plus hilar lymph nodes and adjacent para-aortic nodes, and the planning target volume included clinical target volume plus 1 cm. All patients also received a 5-FU infusion of 1000 mg/m2/day for 4 days during week 1 and 5 of the external beam radiotherapy. Additionally, for 2 weeks of every 3 while awaiting OLT, they received maintenance capecitabine at a dose of 2000 mg/m2/day.

Following completion of neoadjuvant treatment, all patients were restaged radiologically with a CT-TAP, and in the absence of metastatic disease, a restaging laparotomy or laparoscopy was subsequently performed as previously described. All patients were then formally rediscussed at the multidisciplinary transplant meeting and, if suitable, listed for transplantation. A restaging CT-TAP was repeated at 3 monthly intervals while awaiting OLT or sooner if clinically indicated.

Operative Technique

In order to minimize the cold ischemia of the graft, the transplant and the organ procurement team work in parallel. Upon confirmation by the procurement team that the donor organ is suitable for transplantation, the exploratory laparotomy phase in the recipient is commenced. As per the unit’s protocol, a second potential recipient is always on standby, in the event the intended recipient is found to have disease progression at the time of the exploratory laparotomy. Pathological analysis of any suspicious lesions identified during the exploratory laparotomy/hepatectomy phase is performed by frozen section.

Hepatectomy: The standard procedure involves the following steps:

  1. Thorough abdominal exploration to exclude peritoneal metastatic disease, lymphatic involvement, or liver metastases. When extrahepatic malignancy is suspected, frozen sections are performed before proceeding.
  2. Complete clearance of the lymphatic tissue around the hepatic pedicle. Division of the common bile duct as it enters the head of pancreas. Frozen section is obtained from the distal end of the common bile duct. Preservation of the portal vein, with ligation of the hepatic artery just proximal to the origin of the gastroduodenal artery.
  3. A “Roux en Y” jejuno-jejunal anastomosis is created before completion of the hepatectomy.
  4. Creation of an arterial conduit for the arterial inflow of the graft. This step involves anastomosing 1 of the donor’s iliac arteries to the infra renal segment of the recipient’s aorta (Prolene 4.0). The artery is passed through the root of the transverse colon mesentery to be later used for the arterial reconstruction. The use of the native hepatic artery or splenic artery is contraindicated given that all patients have received external beam radiotherapy with or without brachytherapy.
  5. Full mobilization of the native liver. The vena cava is preserved. The hepatic veins are all exposed and selectively controlled and the total hepatectomy completed. This is achieved by clamping and dividing the portal vein just below its bifurcation followed by clamping and dividing all hepatic veins. The liver is removed and the hepatic veins are sutured (Prolene 3.0).

Implantation:

  1. The implantation is performed according to the standard technique of orthotopic LT using either side to side cavo-caval or “Piggy Back” anastomosis (depending on the surgeon’s preferences). Replacement of vena cava is not necessary.
  2. Reconstruction of the portal vein (Prolene 6.0) followed by reperfusion of the graft.
  3. Arterial anastomosis (Prolene 6.0). The level of the arterial anastomosis varies from recipient to recipient.
  4. Biliodigestive anastomosis (PDS 6.0) using the already created Roux en Y loop.

If veno-venous bypass is required, the inferior mesenteric vein is used for the portal flow. The right femoral vein is used for the systemic flow. The cannulation of the femoral vein is done under US guidance (Seldinger technique). For the venous return, the right internal jugular vein or alternatively the left axillary vein are used.

Following transplantation, a standard immunosuppressant maintenance regime of tacrolimus and steroids was used. All patients were followed up with a CT-TAP and CA 19-9 level on a 6-monthly basis for the first 2 years, and annually thereafter. Locoregional recurrence was defined as radiographically or pathologically confirmed evidence of cholangiocarcinoma in the hilar or perihilar region posttransplantation. Distant recurrence was defined as that occurring within a solid organ.

2.4 Statistical Analysis

Data were analyzed using SPSS software (PASW 18.0 for Mac, SPSS Inc, Chicago, IL). A significance level of 0.05 was used for all analyses; reported P are 2-tailed. Continuous variables are described as mean (±SD) or median values (range) and compared by the Student t test or Mann-Whitney U test, depending on their distribution. Categorical variables are reported as percentages. Association of categorical variables was assessed using χ2 test or Fisher exact test where appropriate. Survival statistics were calculated using the Kaplan-Meier method, and the log-rank test was used to assess differences in survival between groups. Independent variables were entered into a multivariate binary logistic regression model. Variables that were found at univariate analysis to be significant, or a P < 0.1 were entered into the multivariate model.

RESULTS

Patient Characteristics and Pathology

A total of 37 consecutive patients diagnosed with unresectable hCCA between 2004 and 2016 were enrolled in this study and underwent nCRT. Of those, 11 were excluded due to progression of disease following neoadjuvant treatment (n = 9) or while awaiting OLT (n = 2). A total of 26 patients proceeded to transplantation and comprise the study cohort. Clinical and pathologic characteristics of the study population are shown in Table 1. There were 24 (92%) males and the median age was 49 years. The majority of patients (n = 23) had hCCA arising in the setting of PSC.

TABLE 1. - Clinical and pathological characteristics of study population
N (%)
Age (median, range) 49 (24–67)
Males 24 (92)
PSC 23 (88)
Mean bilirubin at diagnosis, umol/L 87
Mean CA19-9 at diagnosis, U/mL 403
Bismuth Classification
I 4 (15)
II 7 (27)
IIIa 7 (27)
IIIb 6 (23)
IV 2 (8)
pCR 16 (62)
Node negative pathology 24 (92)
R0 resection rate 25 (96)
pCR, complete pathologic response; PSC, primary sclerosing cholangitis.

Preoperative diagnosis of hCCA was established in 24 patients (92%). The remaining 2 patients who did not have a pathologically or cytologically confirmed diagnosis fulfilled the criteria of an elevated CA19-9 (>100 U/mL) in the setting of a radiologically characteristic malignant stricture. The diagnosis of hCCA was later confirmed on histopathological analysis of the explant specimen in both patients.

The neoadjuvant treatment protocol was completed in 58% of patients. While all patients received external beam radiotherapy and chemotherapy, 11 patients (42%) did not receive brachytherapy due to technical difficulties placing the transhepatic catheter. The mean and median time to transplant were 90 and 71 (range 1–294) days, respectively. Fourteen patients were transplanted within 3 months of listing, 9 were transplanted between 3 and 6 months, and the remaining 3 between 6 and 12 months.

Overall, 16 (62%) patients achieved a complete pathologic response (pCR), 92% were node negative, and the R0 resection rate was 96%. In terms of histopathologic analysis of the explant, pathological characteristics such as tumor regression grade and perineural invasion were not routinely reported throughout the study period.

Mortality

In-hospital mortality was 15% (n = 4). The 4 deaths occurred at 3, 35, 55, and 109 days, postoperatively. The first patient developed primary graft nonfunction and had a cardiorespiratory arrest following retransplant. The second patient developed disseminated intravascular coagulation and multiorgan failure, while the third patient developed hepatic artery thrombosis (HAT). The fourth patient underwent retransplant for HAT, had a significant postoperative hepatic artery bleed and pancreatic leak requiring multiple laparotomies, before succumbing to sepsis.

Survival

After a median follow-up of 67 months (24–158), median overall survival was 53 months, with a 1-year OS of 81%, 3-year OS of 69%, and a 5-year OS of 55%. The median survival of the entire cohort of 37 patients was 21.8 months, with OS at 1, 3, and 5 years 68%, 48%, and 38%, respectively. Disease-free survival at 1, 3, and 5 years was 76%, 63%, and 52%, respectively. The survival data are presented in Table 2 and Figures 1, 2, and 3.

TABLE 2. - Intention to treat and as treated overall survival data
Analysis 1-y OS, % 3-y OS, % 5-y OS, %
Intention to treat (n = 37) 68 48 38
As-treated (n = 26) 81 69 55
OS, overall survival.

FIGURE 1.
FIGURE 1.:
Overall survival as treated. Kaplan-Meier curve representing the overall survival of the 26 patients who proceeded to transplant.
FIGURE 2.
FIGURE 2.:
Overall survival intention to treat. Kaplan-Meier curve representing the overall survival of the entire cohort of 37 patients who commenced neoadjuvant chemoradiotherapy. pCR, complete pathologic response.
FIGURE 3.
FIGURE 3.:
Kaplan-Meier curve comparing the survival of patients who developed metastatic disease during neoadjuvant therapy to those who completed the Mayo Protocol. OLT, orthotopic liver transplantation.

Of the 26 patients who proceeded to OLT, 13 are still alive. The cause of death for the remaining 13 are as follows; 4 in-hospital deaths as described, 6 died as a result of disease recurrence, 1 died from Burkitt lymphoma, 1 from metastatic lung cancer, and 1 from metastatic gastric adenocarcinoma. Among the 16 patients who achieved a pCR, 4 have died. Only 1 of these patients developed distant disease recurrence, 2 had in-hospital deaths, and 4 died of metastatic gastric cancer. Of the 2 patients who were node-positive on final pathology, both have died. One was an in-hospital mortality from disseminated intravascular coagulation and multiorgan failure, and the other patient developed locoregional recurrence and died 57 months posttransplant.

Patients who attained a pCR had a significantly longer median survival than patients who did not achieve a pCR; 83.8 months versus 20.9 months (P = 0.036, Figure 4). Among the patients who developed metastatic disease during neoadjuvant treatment, overall survival at 1, 3, and 5 years was 36.1%, 0%, and 0%, respectively. Their median survival was 10.5 months, compared with 53 months in patients who proceeded to transplant (P < 0.001; Figure 4).

FIGURE 4.
FIGURE 4.:
Kaplan-Meier curve comparing the survival of patients who achieved a complete pathological response to those who did not. pCR, complete pathologic response.

Disease Recurrence

A total of 6 patients (23%) developed disease recurrence, and all have died as a result. Of these, 3 patients developed locoregional recurrence and 3 patients developed distant disease. The median time to recurrence was 19 months from transplantation. The incidence of disease recurrence in patients who did not achieve a pCR was 50% compared with 6.3% in patients who did achieve pCR (P = 0.01).

There was no significant difference in disease recurrence rate among patients who waited >90 days for transplant and those who waited <90 days (P = 0.652).

Morbidity

Vascular Complications

Overall, 6 patients developed HAT. Of those, 3 required a retransplantation, 1 underwent angioplasty and anticoagulation, and 2 received palliative measures only.

Biliary Complications

Three patients developed a postoperative bile leak. One was managed conservatively while another required percutaneous drainage by interventional radiology and the third patient required reoperation and had placement of a T-tube. A further patient developed a biliary stricture requiring percutaneous transhepatic cholangiography in interventional radiology.

Retransplantation

Five patients required retransplantation (19.2%). The indications for retransplant were HAT (n = 3), portal venous thrombosis (n = 1), and hepatic ischemia, secondary to hemorrhage from the hepatic artery (n = 1). Seven patients required a combined OLT and Whipple procedure, the indications for which were involvement of the distal common bile duct (n = 2) and extensive radiation induced fibrosis precluding standard resection (n = 5).

Prognostic Factors

Univariable logistic regression of factors predicting disease recurrence and survival are presented in Table 3. On multivariable analysis, only pathological complete response was significantly associated with disease recurrence and overall survival, P = 0.006.

TABLE 3. - Univariable logistic regression of factors predicting residual disease, disease recurrence, and survival
Residual CCA CCA recurrence Survival
Variable P HR P HR P HR
Gender (females) 0.92 0.16 0.41 0.76 0.76 1.0
Elevated CA19-9 at diagnosis 0.65 0.87 0.08 3.4 0.21 1.55
Age >55 y 0.42 1.78 0.51 0.19 0.06 4.06
Lesion >3 cm 0.85 0.34 0.68 0.90 0.30 1.23
Brachytherapy 0.62 0.99 0.58 0.90 0.34 0.65
Wait time to transplant >90 days 0.46 1.59 0.40 1.50 0.65 1.0
Associated Whipple procedure 0.27 2.74 0.18 1.96 0.04 5.2
R0 resection 0.23 3.1 0.50 1.4
Node positive (final pathology) 0.92 0.16 0.42 0.80 0.24 2.9
pCR 0.38 1.98 0.02 6.75 0.002 11.5
CCA, cholangiocarcinoma; HR, hazard ratio; pCR, complete pathologic response.

DISCUSSION

Liver transplantation is the only potentially curative treatment option for unresectable hCCA. Poor long-term survival and high recurrence rates observed with transplantation alone led to the development of a multimodal approach. Pioneered by the Mayo Clinic, combined modality therapy consisting of nCRT followed by liver transplantation has been shown to achieve superior oncologic outcomes. The Mayo Clinic have now treated 319 patients per this protocol and have performed 199 transplants, with 5-year survival rates of 56% observed among patients with de novo hCCA and 76% for hCCA in the setting of PSC.17 Similar encouraging results have been demonstrated in other centers, with 5-year recurrence-free survival rates of 65% reported in a recent multicenter study including data from 12 institutions.16 In this multicenter analysis, although 193 of 287 patients were treated at the Mayo Clinic, no significant differences in outcomes were identified when Mayo Clinic data were compared with all other centers combined.

Despite this encouraging survival data, concerns exist regarding reproducibility of these results, the intensity and tolerability of the neoadjuvant protocol, and the justification of scarce resource allocation. To the best of our knowledge, we present the largest single-center European experience of nCRT followed by liver transplantation for unresectable hCCA, de novo or in the setting of PSC. Among 26 patients who underwent transplantation, after a median follow-up of 67 months, the median overall survival was 53 months, with a 5-year survival of 55%. On multivariate analysis, pathologic response to nCRT was significantly associated with survival (P < 0.05).

Due to the scarcity of available liver grafts and ethical implications of their allocation, identifying patients most likely to benefit from transplantation is of great importance. Despite an intense neoadjuvant therapy regimen, tumor recurrence remains a significant challenge and represents the leading cause of death among patients who undergo transplantation for hCCA. In this series, 23% of patients developed disease recurrence at a median interval of 19 months from transplantation and all have died. Pathologic response to neoadjuvant therapy has been well established as an important predictor of favorable outcome and the presence of residual tumor in the explant specimen has been shown to correlate significantly with disease recurrence and lower 5-year survival.20-22 In this series, achievement of a pCR, conferred a marked survival advantage. It is clear that individual patients’ response to neoadjuvant therapy varies significantly and that identifying predictors of pathologic response would be hugely beneficial in guiding therapeutic decisions and patient selection.

Additional factors that have been associated with development of disease recurrence include older age, prior cholecystectomy, portal vein encasement, residual tumor on explant (>2 cm), and unfavorable pathologic characteristics (perineural and lymphovascular invasion).20 Previous studies have also identified pretransplant CA19-9 level as a predictor of disease recurrence.20,21 It has been postulated that an elevated CA 19-9 level following neoadjuvant therapy may represent a surrogate marker of aggressive tumor biology and inherent chemoresistance, and so may be a proxy of histopathologic response. In our previous report, a pretransplant CA 19-9 level >100 U/mL was associated with a significantly increased risk of tumor in the explant specimen.19 In this analysis, however, there was no association with pretransplant CA19-9 level and residual tumor or disease recurrence. There was also no association between a longer interval to transplant and pathological response or disease recurrence.

Despite the clear survival advantage associated with the Mayo protocol, concerns exist surrounding the dose-related toxicity and perioperative morbidity and mortality associated with its neoadjuvant treatment regime. The oncological benefits of high-dose radiotherapy, must be weighed against the resultant radiation-induced fibrosis which can lead to more technically challenging dissection. The proportion of patients in this series requiring a simultaneous Whipple procedure has decreased substantially over time. No combined resections were performed in the latter half of the series. This is predominantly related to a decrease in radiation-induced fibrosis around the hepatic pedicle, after the external beam radiation dose was changed from 55 to 45 Gy, limiting the extent of resection required. Importantly, pathological response and recurrence rates have not been negatively affected by this change in the radiation protocol. Furthermore, 42% of patients in this series did not receive brachytherapy. When compared with those who did, there were no significant differences in pathological response, disease recurrence, or survival.

Since the publication of our initial data in 2014, there have been no additional in-hospital deaths. The relatively high in-hospital mortality rate experienced initially may have been related to the number of patients who required a combined Whipple procedure and OLT early in the series. All of the in-hospital deaths occurred in patients who underwent either a simultaneous Whipple procedure or redo OLT, both of which are highly morbid procedures. The in-hospital mortality rate for noncholangiocarcinoma OLTs performed in this institution during the same time period is significantly lower at 3%, as is the HAT rate (2%–3% for all other OLTs). Possible explanations for this discrepancy in HAT rate include the high number of combined Whipple procedures, the significant proportion of patients with PSC, the inflammatory nature of which is prothrombotic, and the lack of standardized perioperative prophylactic anticoagulation early in the series.

The dropout rate in this series was 30%, similar to that reported by other centers.21,23 Among the 11 patients who became ineligible for transplantation following completion of neoadjuvant therapy, survival was poor. Median survival of 10 months is comparable with that observed with palliative chemotherapy.24-26 The majority (82%) of patients became ineligible for transplant due to the finding of metastatic disease at surgical staging. These findings are in keeping with those reported by the Mayo Clinic and highlight the importance of surgical staging before transplantation.27 The optimal timing of surgical staging, however, remains less clear. The Mayo Clinic have described performing surgical staging as the patient nears the top of the surgical waiting list, or on the day before living donor transplantation.27 In this study, however, surgical staging, increasingly by laparoscopy, was performed before enrollment to the protocol and following completion of neoadjuvant therapy before listing for transplantation to ensure accurate patient selection.

The field of transplant oncology has certainly gained great momentum over the past 2 decades. As the indications for liver transplantation evolve, the ethical debate continues, however, regarding the justification of allocating scarce liver grafts in oncology.13,28 Encouragingly, long-term outcomes of transplantation for unresectable hCCA are now comparable with other indications and exceed the minimum requirement of 50% survival at 5 years. Advances in the medical treatment of hepatitis C virus, namely the development of direct-acting antiviral agents, have dramatically decreased the need for transplantation among this patient cohort.29 Any resultant increase in the organ pool is likely to be offset, however, by the significant rise in incidence of cirrhosis related to nonalcoholic steatohepatitis in the western world.30 Furthermore, optimization of immunosuppressant regimes has led to substantial improvements in long-term outcomes among patients undergoing liver transplantation for hepatitis C virus, emphasizing the need to accurately select patients to justify resource allocation.29,31 In an era of personalized medicine, characterization of the biological profile of the tumor and identification of molecular biomarkers that would aid prediction of treatment response, would enable selection of patients likely to derive a meaningful benefit from such a management approach. This could reduce the inappropriate utilization of liver grafts in patients with treatment-resistant disease who are unlikely to have a favorable outcome post-OLT. With continuing advancements in genomics and molecular profiling, this will hopefully become a reality in the not too distant future.

This study has several limitations, including small study size and relatively short follow-up overall. Nonetheless, the results support the role of nCRT followed by liver transplantation in the management of unresectable de novo hCCA or hCCA arising in the setting of PSC. Pathological response to neoadjuvant therapy represented the most important predictor of outcome, highlighting the importance of identifying pretreatment molecular biomarkers to predict response and guide patient selection.

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