Neoadjuvant Chemoradiation for Perihilar Cholangiocarcinoma
Neoadjuvant Chemoradiation for Perihilar Cholangiocarcinoma
Background & Aims Excellent single-center outcomes of neoadjuvant chemoradiation and liver transplantation for unresectable perihilar cholangiocarcinoma caused the United Network of Organ Sharing to offer a standardized model of end-stage liver disease (MELD) exception for this disease. We analyzed data from multiple centers to determine the effectiveness of this treatment and the appropriateness of the MELD exception.
Methods We collected and analyzed data from 12 large-volume transplant centers in the United States. These centers met the inclusion criteria of treating 3 or more patients with perihilar cholangiocarcinoma using neoadjuvant therapy, followed by liver transplantation, from 1993 to 2010 (n = 287 total patients). Center-specific protocols and medical charts were reviewed on-site.
Results The patients completed external radiation (99%), brachytherapy (75%), radiosensitizing therapy (98%), and/or maintenance chemotherapy (65%). Seventy-one patients dropped out before liver transplantation (rate, 11.5% in 3 months). Intent-to-treat survival rates were 68% and 53%, 2 and 5 years after therapy, respectively; post-transplant, recurrence-free survival rates were 78% and 65%, respectively. Patients outside the United Network of Organ Sharing criteria (those with tumor mass >3 cm, transperitoneal tumor biopsy, or metastatic disease) or with a prior malignancy had significantly shorter survival times (P < .001). There were no differences in outcomes among patients based on differences in surgical staging or brachytherapy. Although most patients came from 1 center (n = 193), the other 11 centers had similar survival times after therapy.
Conclusions Patients with perihilar cholangiocarcinoma who were treated with neoadjuvant therapy followed up by liver transplantation at 12 US centers had a 65% rate of recurrence-free survival after 5 years, showing this therapy to be highly effective. An 11.5% drop-out rate after 3.5 months of therapy indicates the appropriateness of the MELD exception. Rigorous selection is important for the continued success of this treatment.
Perihilar cholangiocarcinoma is a highly aggressive malignancy with features of biliary epithelial differentiation. Anatomically perihilar cholangiocarcinoma is defined by disease occurring above the junction of the cystic duct up to the secondary branches of the right and left hepatic ducts. It is the second most common primary liver cancer with an annual incidence of 1.2/100,000 in the United States. Historically, treatment options for this devastating disease have been limited. Resection is the standard of care, although many patients present with unresectable disease as a result of involvement of bilateral hilar structures or underlying parenchymal liver disease (primary sclerosing cholangitis). Even when resection is possible, the 5-year survival rate is only 20%–40%. Although initially endorsed as an indication for orthotopic liver transplantation (LT), the experience with LT alone was disappointing owing to a high rate of tumor recurrence (53%–84%) and, thus, perihilar cholangiocarcinoma became a contraindication to LT.
However, inspired by small reports of long-term survival noted in patients who received radiotherapy alone, first the University of Nebraska, and later the Mayo Clinic, developed a protocol using neoadjuvant chemoradiation followed by LT. This protocol includes selected patients with unresectable early stage (stages I–II) perihilar cholangiocarcinoma, who consecutively undergo external beam radiotherapy (EBRT) combined with radiosensitizing chemotherapy (ie, 5-flouracil), brachytherapy with endoscopically placed iridium-192 beads, maintenance chemotherapy (ie, oral capecitabine), staging surgery to rule out metastases, and, finally, LT. Subsequent reports consistently showed 5-year, recurrence-free survival of approximately 70%. Encouraged by these outcomes, in June 2009 the United Network of Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) approved the allocation of a standard model of end-stage liver disease (MELD) exception score for patients with perihilar cholangiocarcinoma who completed an approved neoadjuvant therapy protocol. Hampered by lack of data, the MELD score was set to equal the current standard assigned score for hepatocellular carcinoma, representing an expected 10% increase in waitlist mortality every 3 months.
Information on how many centers in the United States are actively transplanting these patients, what type of neoadjuvant therapy is being used, and, most importantly, what outcomes are achieved, currently is unknown. Given the severe shortage of donor organs, these data are crucial to determine whether use of liver allografts for this indication is justified and, if so, what the appropriate waitlist priority should be. Therefore, we examined the US experience to achieve the following: (1) evaluate the overall effectiveness of neoadjuvant therapy followed by LT for perihilar cholangiocarcinoma; (2) assess the impact of intercenter variance in selection and neoadjuvant therapies; and (3) determine whether the current MELD exception score is appropriate.
Abstract and Introduction
Abstract
Background & Aims Excellent single-center outcomes of neoadjuvant chemoradiation and liver transplantation for unresectable perihilar cholangiocarcinoma caused the United Network of Organ Sharing to offer a standardized model of end-stage liver disease (MELD) exception for this disease. We analyzed data from multiple centers to determine the effectiveness of this treatment and the appropriateness of the MELD exception.
Methods We collected and analyzed data from 12 large-volume transplant centers in the United States. These centers met the inclusion criteria of treating 3 or more patients with perihilar cholangiocarcinoma using neoadjuvant therapy, followed by liver transplantation, from 1993 to 2010 (n = 287 total patients). Center-specific protocols and medical charts were reviewed on-site.
Results The patients completed external radiation (99%), brachytherapy (75%), radiosensitizing therapy (98%), and/or maintenance chemotherapy (65%). Seventy-one patients dropped out before liver transplantation (rate, 11.5% in 3 months). Intent-to-treat survival rates were 68% and 53%, 2 and 5 years after therapy, respectively; post-transplant, recurrence-free survival rates were 78% and 65%, respectively. Patients outside the United Network of Organ Sharing criteria (those with tumor mass >3 cm, transperitoneal tumor biopsy, or metastatic disease) or with a prior malignancy had significantly shorter survival times (P < .001). There were no differences in outcomes among patients based on differences in surgical staging or brachytherapy. Although most patients came from 1 center (n = 193), the other 11 centers had similar survival times after therapy.
Conclusions Patients with perihilar cholangiocarcinoma who were treated with neoadjuvant therapy followed up by liver transplantation at 12 US centers had a 65% rate of recurrence-free survival after 5 years, showing this therapy to be highly effective. An 11.5% drop-out rate after 3.5 months of therapy indicates the appropriateness of the MELD exception. Rigorous selection is important for the continued success of this treatment.
Introduction
Perihilar cholangiocarcinoma is a highly aggressive malignancy with features of biliary epithelial differentiation. Anatomically perihilar cholangiocarcinoma is defined by disease occurring above the junction of the cystic duct up to the secondary branches of the right and left hepatic ducts. It is the second most common primary liver cancer with an annual incidence of 1.2/100,000 in the United States. Historically, treatment options for this devastating disease have been limited. Resection is the standard of care, although many patients present with unresectable disease as a result of involvement of bilateral hilar structures or underlying parenchymal liver disease (primary sclerosing cholangitis). Even when resection is possible, the 5-year survival rate is only 20%–40%. Although initially endorsed as an indication for orthotopic liver transplantation (LT), the experience with LT alone was disappointing owing to a high rate of tumor recurrence (53%–84%) and, thus, perihilar cholangiocarcinoma became a contraindication to LT.
However, inspired by small reports of long-term survival noted in patients who received radiotherapy alone, first the University of Nebraska, and later the Mayo Clinic, developed a protocol using neoadjuvant chemoradiation followed by LT. This protocol includes selected patients with unresectable early stage (stages I–II) perihilar cholangiocarcinoma, who consecutively undergo external beam radiotherapy (EBRT) combined with radiosensitizing chemotherapy (ie, 5-flouracil), brachytherapy with endoscopically placed iridium-192 beads, maintenance chemotherapy (ie, oral capecitabine), staging surgery to rule out metastases, and, finally, LT. Subsequent reports consistently showed 5-year, recurrence-free survival of approximately 70%. Encouraged by these outcomes, in June 2009 the United Network of Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) approved the allocation of a standard model of end-stage liver disease (MELD) exception score for patients with perihilar cholangiocarcinoma who completed an approved neoadjuvant therapy protocol. Hampered by lack of data, the MELD score was set to equal the current standard assigned score for hepatocellular carcinoma, representing an expected 10% increase in waitlist mortality every 3 months.
Information on how many centers in the United States are actively transplanting these patients, what type of neoadjuvant therapy is being used, and, most importantly, what outcomes are achieved, currently is unknown. Given the severe shortage of donor organs, these data are crucial to determine whether use of liver allografts for this indication is justified and, if so, what the appropriate waitlist priority should be. Therefore, we examined the US experience to achieve the following: (1) evaluate the overall effectiveness of neoadjuvant therapy followed by LT for perihilar cholangiocarcinoma; (2) assess the impact of intercenter variance in selection and neoadjuvant therapies; and (3) determine whether the current MELD exception score is appropriate.
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