The Mayo Clinic neoadjuvant therapy and liver transplantation protocol was developed in 1993 with an aim to provide effective treatment for patients with unresectable hilar cholangiocarcinoma (CCA) or CCA arising in the setting of PSC. Prior to that time, results of treatment with liver transplantation alone were very poor. CCA had become recognized as an absolute contraindication for liver transplantation, and patients with primary sclerosing cholangitis (PSC) were carefully evaluated to rule-out CCA prior to transplantation.
Protocol rationale
The protocol was designed to achieve the best possible chance for success in order to demonstrate efficacy and justify use of donor livers. We developed firm inclusion and exclusion criteria and adopted strict adherence to protocol. The protocol involves neoadjuvant therapy with high dose external beam radiotherapy and brachytherapy, operative staging to exclude occult extrahepatic disease prior to transplantation, and subsequent liver transplantation.
The rationale for the protocol is based on the known palliative efficacy of high dose radiotherapy in slowing progression of CCA. Operative staging was included to avoid transplantation for patients with regional lymph node involvement. The decision to perform the staging operation after neoadjuvant therapy was made with a theoretical aim to avoid tumor dissemination during the staging and transplant procedures. Liver transplantation achieves the most radical resection possible and replaces a liver damaged by neoadjuvant therapy (and often PSC as well).
Criteria for treatment
CCA is difficult to confirm with pathology. We adopted clinical criteria to assure that nearly all patients indeed have CCA and that patients with tumors difficult to pathologically confirm do not suffer from delays in diagnosis and treatment. Diagnosis requires a malignant-appearing stricture on cholangiography and at least one of the following: 1) cytology or histology demonstrating adenocarcinoma; 2) visualization of a mass at the location of the stricture on cross-sectional imaging; CA-19.9 > 100U/mL; or 3) polysomy by fluorescence in-situ hybridization (FISH).
All patients are required to have unresectable CCA and/or CCA arising in the setting of PSC. We include patients with CCA arising in PSC (even if potentially resectable) due to the poor natural history of the disease combination and concern for multicentric carcinoma. We originally required that the tumor not extend below the cystic duct, but we later found that patients with microscopic disease extending below the cystic duct could be treated with pancreatoduodenectomy during liver transplantation. We continue to exclude patients with mass lesions extending below the cystic duct due to the high probability that the tumor could involve the portal vein precluding complete extirpation of tumor.
The Mayo Clinic protocol specifically excludes patients with either intrahepatic or extrahepatic metastases, gall bladder involvement, intrahepatic CCA, or other conditions precluding liver transplantation. The protocol also excludes patients with radial tumor diameter (diameter perpendicular to the ducts) exceeding 3cm. Vascular encasement and longitudinal extension of tumor along the duct (provided that it does not extend below the cystic duct) are not contraindications for treatment. We also learned to exclude patients with a prior exploration for resection or a transperitoneal fine needle aspiration of the primary tumor (done to establish a diagnosis) as nearly all of these patients were either found to have peritoneal seeding at operative staging or developed recurrent disease after transplantation.
Neoadjuvant therapy
Patients are treated with high dose radiotherapy, IV 5-FU for radiosensitization, and brachytherapy. Capecitabine is prescribed as tolerated while patients await transplantation. The morbidity associated with neoadjuvant therapy is significant. Nearly all patients experience at least one episode of cholangitis. Other complications include cholecystitis, duodenal ulceration with bleeding and perforation, gastric outlet obstruction, and liver failure in addition to the commonly expected complications of radiotherapy and chemotherapy.
Operative staging
Operative staging is best performed as the time nears for deceased donor transplantation or the day before living donor transplantation. The procedure can be done with hand-assisted laparoscopy. After careful exploration for peritoneal disease or intrahepatic metastases not detected by cross-sectional imaging, lymph nodes are excised (even if they appear benign) along the common hepatic artery at the take-off of the gastroduodenal artery and along the common bile duct. The hilus is palpated to determine whether the tumor involves the caudate, a finding that could require replacement of the retrohepatic inferior vena cava during transplantation. Approximately 20% of patients are found to have regional lymph node or other metastases which preclude transplantation.
Liver transplantation
Differences between transplantation for CCA after neoadjuvant therapy and transplantation for other indications include the following: 1) avoidance of the hilus with low division of the portal vein which requires a deceased donor iliac vein as an interposition graft during living donor liver transplantation; 2) use of an iliac artery graft to the infrarenal aorta to avoid use of the irradiated native common hepatic artery during deceased donor transplantation; 3) frozen section examination of the common bile duct margin in patients with underlying PSC since there is a 10 – 15% chance that it could have microscopic involvement; and 4) biliary reconstruction with a Roux-en-Y choledochojejunostomy (instead of a choledochoduodenostomy due to irradiation of the duodenum).
Incidences of arterial and portal complications after liver transplantation for CCA are higher than following transplantation for other indications due to the high dose radiotherapy administered prior to transplantation. Portal vein stenosis develops within four months for approximately 20% of patients. It is readily treatable with transhepatic angioplasty and stentinsertion. We avoid arterial problems by using an iliac artery graft to the infrarenal aorta during deceased donor transplantation. With living donor liver transplantation, we do an end-to-end anastomosis between the donor and recipient arteries but observe the recipients closely afterward by serial ultrasonography to monitor for stenosis and allow early intervention.
Ten to 15% of patients with CCA arising in PSC will have microscopic tumor involvement of the common bile duct margin. Pancreatoduodenectomy significantly increases the morbidity of transplantation, but it does result in the possibility of prolonged survival. We have occasionally performed a planned en bloc pancreatoduodenectomy/hepatectomy during transplantation for patients with known microscopic disease involving the common bile duct or technical considerations (such as a prior choledochoduodenostomy), but we do so with extreme caution. In total, we have done 19 pancreatoduodenectomies including 5 during living donor liver transplantation. We have had 3 early (within 3 months) deaths due to perioperative complications and 7 late (after 3 months) deaths – 3 from recurrent CCA, 2 from other malignancies, and 2 from perioperative complications. Overall 5-year survival after transplantation is 37%, which is well below our results overall and for CCA arising in PSC.
Results
Three hundred nineteen patients began neoadjuvant therapy at Mayo Clinic Rochester since 1993 – 197 with CCA arising in PSC and 122 with CCA arising de novo. Two hundred sixty-one have undergone operative staging, and 21% had findings precluding subsequent transplantation. 199 underwent liver transplantation – 129 with deceased donors, 68 with living donor livers (58 right and 10 left liver grafts), and 1 with a domino liver graft from a patient with familial amyloidosis. Patients with CCA arising in the setting of PSC fare better than those with de novo CCA. 16% of the patients with CCA arising in PSC staged positive compared to 28% of those with CCA arising de novo. Five year patient survival from the start of neoadjuvant therapy (intention-to-treat analysis) was 60% for 171 patients with CCA arising in PSC and 37% for 112 patients with CCA arising de novo. Five year survival after transplantation was 77% for 113 patients with CCA arising in PSC and 56% for 68 patients with CCA arising de novo. During follow-up, recurrent disease developed in 16% of patients with CCA arising in PSC and 40% of patients with CCA arising de novo. These results have been corroborated by two multicenter studies in the US.
The results achieved with neoadjuvant therapy and liver transplantation clearly justify consideration of this treatment for patients with CCA arising in PSC. Patient survival after the start of neoadjuvant therapy greatly exceeds the natural history of CCA arising in PSC and results with liver transplantation alone. Patient survival after transplantation is comparable to results achieved with transplantation for other malignant and benign conditions and clearly justifies use of scarce deceased donor livers and living donor livers for this condition. Neoadjuvant therapy and liver transplantation has emerged as the treatment of choice for patients with CCA within treatment criteria.
The results achieved with neoadjuvant therapy and liver transplantation also clearly justify consideration of this treatment for patients with unresectable CCA arising de novo. Five year survival from the start of neoadjuvant therapy is 37%. Our experience and other transplant experiences reported to date are with patients that have been deemed to have unresectable disease, and these patients do not have any other option for potentially curative treatment. Five year survival after transplantation is 55%. Although that survival is below results achieved with transplantation for other conditions, it exceeds 50% - which many consider a “reasonable chance for success” and the survival threshold necessary to justify use of a deceased or living donor liver.
The excellent results achieved with neoadjuvant therapy and liver transplantation have sparked a much more controversial debate – whether patients with potentially resectable CCA should be treated with resection or neoadjuvant therapy and transplantation. A randomized prospective trial comparing resection to neoadjuvant therapy and transplantation is ongoing in France, and the results of that trial will lead to more clarity. If neoadjuvant therapy and transplantation is shown to have significantly better results than resection, the key issue will be how much better the results should be in order to justify use of deceased and living donor livers for this treatment.
My personal opinion is that patients with potentially resectable CCA should be treated with resection. If there is a survival advantage for patients with potentially resectable CCA treated with the transplant protocol, the survival benefit over resection is likely less than 10 to 20% at five years. This potential benefit is much less than the standard 50% 5-year survival expectation for liver transplantation which is essentially a survival benefit (because most transplant candidates are not expected to survive for five years without transplantation).
Key points
• Neoadjuvant therapy and liver transplantation is effective treatment for selected patients with early stage unresectable CCA and CCA arising in the setting of PSC
• Neoadjuvant therapy is crucial to the treatment protocol and results in an inability to detect residual cancer in the explanted liver for half of the patients
• Patient survival five years after transplantation exceeds 75% for patients with CCA arising in PSC and 55% for patients with CCA arising de novo and justifies use of scarce deceased and living donor livers for the treatment of these conditions
• Success requires strict adherence to selection criteria and treatment protocol
• Neoadjuvant therapy is associated with significant morbidity and mortality
• Operative staging is essential prior to transplantation as 20% of patients will have findings precluding transplantation
• Transplantation following neoadjuvant therapy requires specific technical adjustments to standard transplantation
• The common bile duct margin should be examined by frozen section for patients with CCA arising in PSC and it is reasonable to proceed with pancreatoduodenectomy in this situation
• Vascular complications involving the portal vein and the hepatic artery are more frequent than after transplantation for other indications due to neoadjuvant therapy