Perihilar Cholangiocarcinoma: Neoadjuvant Therapy and Liver Transplant Effective

Neoadjuvant chemoradiation followed by liver transplantation is an effective and appropriate strategy for treating unresectable perihilar cholangiocarcinoma, according to a multicenter, retrospective study reported by Dr. Sarwa Darwish Murad and her colleagues in the July issue of Gastroenterology.

Historically, treatment options for the highly aggressive malignancy have been limited because many patients present with unresectable disease, and even among those in whom resection is possible, 5-year survival rates have been low. Further, the efficacy of orthotopic liver transplantation in these patients has been compromised by a high rate of tumor recurrence, and thus the disease has been considered a contraindication to the procedure, the authors wrote (Gastroenterology 2012 July [doi: 10.1053/j.gastro.2012.04.008]).

In 2006, based on reports of excellent single-center outcomes of the chemoradiation/transplantation protocol, the United Network of Organ Sharing (UNOS) developed a standardized Model of End-stage Liver Disease (MELD) exception for perihilar cholangiocarcinoma (Liver Transpl. 2006;12:S95-7).

In the current study, Dr. Murad of the Mayo Clinic in Rochester, Minn., and her coinvestigators analyzed data from 12 large-volume transplant centers in the United States that had treated three or more perihilar cholangiocarcinoma patients with neoadjuvant therapy and liver transplantation during 1993-2010.

A total of 287 patients met the study criteria. External radiation, brachytherapy, radiosensitizing therapy, and maintenance chemotherapy were completed by 99%, 75%, 98%, and 65%, respectively. Prior to liver transplantation, 71 patients (24.7%) dropped out after a median of 4.6 months. In the first 3.5 months of therapy, 11.5% dropped out, demonstrating the appropriateness of the MELD exception.

The median follow-up from the time of listing for transplantation was 2.5 years. During this period, 122 patients died after a median of 1.2 years from presentation. Of these deaths, 60 (49%) occurred prior to transplant, and resulted from tumor progression (52), liver failure (3), cardiovascular causes (2), multiorgan failure (2), and sepsis (1). Post transplant, 43 (20%) patients developed recurrence and 62 (22%) patients died, including those whose death was attributed to recurrence (40), sepsis (8), multiorgan failure (3), liver failure (3), post-transplant lymphoproliferative disease (2), and other causes (6).

Post transplant, the 2-, 5-, and 10-year recurrence-free survival rates were 78%, 65%, and 59%, respectively, "demonstrating this therapy to be highly effective," the authors said. No significant differences in recurrence-free survival were observed between patients who underwent deceased vs. living donor transplantation, or in patients with underlying primary sclerosing cholangitis compared with those without.

But survival times were significantly shorter for patients who did not meet the UNOS criteria, including those with a tumor greater than 3 cm, transperitoneal tumor biopsy, or metastatic disease. Specifically, the hazard ratio for patients transplanted outside of the current MELD exception criteria was 2.98 relative to those within the criteria. "Mass size caused the greatest disparity, with 5-year recurrence-free survival of 32% for those larger than 3 cm compared to 69% for smaller tumors," they wrote.

No significant differences were observed between patients who underwent operative staging and those who did not, nor was the timing of staging significantly associated with survival, the authors wrote. Similarly, recurrence-free survival for patients who had received brachytherapy did not differ from that of those who did not.

In an analysis of possible center effects, the investigators determined that there were no significant differences in recurrence-free survival despite the fact that one center contributed the largest number of patients (193). In a multivariate Cox regression model, "selection remained the only significant determinant of recurrence-free survival," according to the authors. In fact, they added, not only is selection the only variable that acts as an independent predictor of outcome and is modifiable at the same time, but "by adjusting selection alone, 5-year recurrence-free survival can be maximized to 72%."

The unadjusted 5-year disease-free survival rate of 65% "is not only similar to results from earlier single-center series but also similar to outcomes of liver transplantation for other malignant and nonmalignant indications," the authors wrote. In addition, the average 3-month dropout rate of 11.5% approximates the expected 10% (as per the standardized MELD exception score equivalent), and as such justifies "using scarce liver allografts for this otherwise lethal disease," they said.

The study is limited by its retrospective design and the fact that a large number of patients (193) came from one center, the authors acknowledged. Also, "due to heterogeneity in duration, type, and dose of maintenance chemotherapy administered at different centers, we were unable to determine the independent impact of maintenance chemotherapy," they wrote.

Although the findings confirm the excellent outcomes of neoadjuvant chemoradiation followed by liver transplantation in patients with perihilar cholangiocarcinoma, an important challenge for the future will be to "gain a greater understanding of the tumor biology in order to reduce wait-list dropout and post-transplant recurrence, either by further refinements in patient selection or, ideally, by more effective chemoradiotherapy," the authors concluded.

The authors had no financial conflicts of interest to disclose.

Neoadjuvant chemoradiation followed by liver transplantation is an effective and appropriate strategy for treating unresectable perihilar cholangiocarcinoma, according to a multicenter, retrospective study reported by Dr. Sarwa Darwish Murad and her colleagues in the July issue of Gastroenterology.

Historically, treatment options for the highly aggressive malignancy have been limited because many patients present with unresectable disease, and even among those in whom resection is possible, 5-year survival rates have been low. Further, the efficacy of orthotopic liver transplantation in these patients has been compromised by a high rate of tumor recurrence, and thus the disease has been considered a contraindication to the procedure, the authors wrote (Gastroenterology 2012 July [doi: 10.1053/j.gastro.2012.04.008]).

In 2006, based on reports of excellent single-center outcomes of the chemoradiation/transplantation protocol, the United Network of Organ Sharing (UNOS) developed a standardized Model of End-stage Liver Disease (MELD) exception for perihilar cholangiocarcinoma (Liver Transpl. 2006;12:S95-7).

In the current study, Dr. Murad of the Mayo Clinic in Rochester, Minn., and her coinvestigators analyzed data from 12 large-volume transplant centers in the United States that had treated three or more perihilar cholangiocarcinoma patients with neoadjuvant therapy and liver transplantation during 1993-2010.

A total of 287 patients met the study criteria. External radiation, brachytherapy, radiosensitizing therapy, and maintenance chemotherapy were completed by 99%, 75%, 98%, and 65%, respectively. Prior to liver transplantation, 71 patients (24.7%) dropped out after a median of 4.6 months. In the first 3.5 months of therapy, 11.5% dropped out, demonstrating the appropriateness of the MELD exception.

The median follow-up from the time of listing for transplantation was 2.5 years. During this period, 122 patients died after a median of 1.2 years from presentation. Of these deaths, 60 (49%) occurred prior to transplant, and resulted from tumor progression (52), liver failure (3), cardiovascular causes (2), multiorgan failure (2), and sepsis (1). Post transplant, 43 (20%) patients developed recurrence and 62 (22%) patients died, including those whose death was attributed to recurrence (40), sepsis (8), multiorgan failure (3), liver failure (3), post-transplant lymphoproliferative disease (2), and other causes (6).

Post transplant, the 2-, 5-, and 10-year recurrence-free survival rates were 78%, 65%, and 59%, respectively, "demonstrating this therapy to be highly effective," the authors said. No significant differences in recurrence-free survival were observed between patients who underwent deceased vs. living donor transplantation, or in patients with underlying primary sclerosing cholangitis compared with those without.

But survival times were significantly shorter for patients who did not meet the UNOS criteria, including those with a tumor greater than 3 cm, transperitoneal tumor biopsy, or metastatic disease. Specifically, the hazard ratio for patients transplanted outside of the current MELD exception criteria was 2.98 relative to those within the criteria. "Mass size caused the greatest disparity, with 5-year recurrence-free survival of 32% for those larger than 3 cm compared to 69% for smaller tumors," they wrote.

No significant differences were observed between patients who underwent operative staging and those who did not, nor was the timing of staging significantly associated with survival, the authors wrote. Similarly, recurrence-free survival for patients who had received brachytherapy did not differ from that of those who did not.

In an analysis of possible center effects, the investigators determined that there were no significant differences in recurrence-free survival despite the fact that one center contributed the largest number of patients (193). In a multivariate Cox regression model, "selection remained the only significant determinant of recurrence-free survival," according to the authors. In fact, they added, not only is selection the only variable that acts as an independent predictor of outcome and is modifiable at the same time, but "by adjusting selection alone, 5-year recurrence-free survival can be maximized to 72%."

The unadjusted 5-year disease-free survival rate of 65% "is not only similar to results from earlier single-center series but also similar to outcomes of liver transplantation for other malignant and nonmalignant indications," the authors wrote. In addition, the average 3-month dropout rate of 11.5% approximates the expected 10% (as per the standardized MELD exception score equivalent), and as such justifies "using scarce liver allografts for this otherwise lethal disease," they said.

The study is limited by its retrospective design and the fact that a large number of patients (193) came from one center, the authors acknowledged. Also, "due to heterogeneity in duration, type, and dose of maintenance chemotherapy administered at different centers, we were unable to determine the independent impact of maintenance chemotherapy," they wrote.

Although the findings confirm the excellent outcomes of neoadjuvant chemoradiation followed by liver transplantation in patients with perihilar cholangiocarcinoma, an important challenge for the future will be to "gain a greater understanding of the tumor biology in order to reduce wait-list dropout and post-transplant recurrence, either by further refinements in patient selection or, ideally, by more effective chemoradiotherapy," the authors concluded.

The authors had no financial conflicts of interest to disclose.

Neoadjuvant chemoradiation followed by liver transplantation is an effective and appropriate strategy for treating unresectable perihilar cholangiocarcinoma, according to a multicenter, retrospective study reported by Dr. Sarwa Darwish Murad and her colleagues in the July issue of Gastroenterology.

Historically, treatment options for the highly aggressive malignancy have been limited because many patients present with unresectable disease, and even among those in whom resection is possible, 5-year survival rates have been low. Further, the efficacy of orthotopic liver transplantation in these patients has been compromised by a high rate of tumor recurrence, and thus the disease has been considered a contraindication to the procedure, the authors wrote (Gastroenterology 2012 July [doi: 10.1053/j.gastro.2012.04.008]).

In 2006, based on reports of excellent single-center outcomes of the chemoradiation/transplantation protocol, the United Network of Organ Sharing (UNOS) developed a standardized Model of End-stage Liver Disease (MELD) exception for perihilar cholangiocarcinoma (Liver Transpl. 2006;12:S95-7).

In the current study, Dr. Murad of the Mayo Clinic in Rochester, Minn., and her coinvestigators analyzed data from 12 large-volume transplant centers in the United States that had treated three or more perihilar cholangiocarcinoma patients with neoadjuvant therapy and liver transplantation during 1993-2010.

A total of 287 patients met the study criteria. External radiation, brachytherapy, radiosensitizing therapy, and maintenance chemotherapy were completed by 99%, 75%, 98%, and 65%, respectively. Prior to liver transplantation, 71 patients (24.7%) dropped out after a median of 4.6 months. In the first 3.5 months of therapy, 11.5% dropped out, demonstrating the appropriateness of the MELD exception.

The median follow-up from the time of listing for transplantation was 2.5 years. During this period, 122 patients died after a median of 1.2 years from presentation. Of these deaths, 60 (49%) occurred prior to transplant, and resulted from tumor progression (52), liver failure (3), cardiovascular causes (2), multiorgan failure (2), and sepsis (1). Post transplant, 43 (20%) patients developed recurrence and 62 (22%) patients died, including those whose death was attributed to recurrence (40), sepsis (8), multiorgan failure (3), liver failure (3), post-transplant lymphoproliferative disease (2), and other causes (6).

Post transplant, the 2-, 5-, and 10-year recurrence-free survival rates were 78%, 65%, and 59%, respectively, "demonstrating this therapy to be highly effective," the authors said. No significant differences in recurrence-free survival were observed between patients who underwent deceased vs. living donor transplantation, or in patients with underlying primary sclerosing cholangitis compared with those without.

But survival times were significantly shorter for patients who did not meet the UNOS criteria, including those with a tumor greater than 3 cm, transperitoneal tumor biopsy, or metastatic disease. Specifically, the hazard ratio for patients transplanted outside of the current MELD exception criteria was 2.98 relative to those within the criteria. "Mass size caused the greatest disparity, with 5-year recurrence-free survival of 32% for those larger than 3 cm compared to 69% for smaller tumors," they wrote.

No significant differences were observed between patients who underwent operative staging and those who did not, nor was the timing of staging significantly associated with survival, the authors wrote. Similarly, recurrence-free survival for patients who had received brachytherapy did not differ from that of those who did not.

In an analysis of possible center effects, the investigators determined that there were no significant differences in recurrence-free survival despite the fact that one center contributed the largest number of patients (193). In a multivariate Cox regression model, "selection remained the only significant determinant of recurrence-free survival," according to the authors. In fact, they added, not only is selection the only variable that acts as an independent predictor of outcome and is modifiable at the same time, but "by adjusting selection alone, 5-year recurrence-free survival can be maximized to 72%."

The unadjusted 5-year disease-free survival rate of 65% "is not only similar to results from earlier single-center series but also similar to outcomes of liver transplantation for other malignant and nonmalignant indications," the authors wrote. In addition, the average 3-month dropout rate of 11.5% approximates the expected 10% (as per the standardized MELD exception score equivalent), and as such justifies "using scarce liver allografts for this otherwise lethal disease," they said.

The study is limited by its retrospective design and the fact that a large number of patients (193) came from one center, the authors acknowledged. Also, "due to heterogeneity in duration, type, and dose of maintenance chemotherapy administered at different centers, we were unable to determine the independent impact of maintenance chemotherapy," they wrote.

Although the findings confirm the excellent outcomes of neoadjuvant chemoradiation followed by liver transplantation in patients with perihilar cholangiocarcinoma, an important challenge for the future will be to "gain a greater understanding of the tumor biology in order to reduce wait-list dropout and post-transplant recurrence, either by further refinements in patient selection or, ideally, by more effective chemoradiotherapy," the authors concluded.

The authors had no financial conflicts of interest to disclose.