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Multicenter Study
. 2012 Jul;143(1):88-98.e3; quiz e14.
doi: 10.1053/j.gastro.2012.04.008. Epub 2012 Apr 12.

Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers

Sarwa Darwish Murad  1 , W Ray Kim, Denise M Harnois, David D Douglas, James Burton, Laura M Kulik, Jean F Botha, Joshua D Mezrich, William C Chapman, Jason J Schwartz, Johnny C Hong, Jean C Emond, Hoonbae Jeon, Charles B Rosen, Gregory J Gores, Julie K Heimbach
Affiliations
Multicenter Study

Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers

Sarwa Darwish Murad et al. Gastroenterology. 2012 Jul.

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.

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Figures

Figure 1
Figure 1
Flow chart of 287 patients with perihilar cholangiocarcinoma who underwent neoadjuvant therapy, staging surgery, and, finally, LT. The outer left boxes represent patients who dropped out from the protocol (total, 71 patients).
Figure 2
Figure 2
Cumulative drop-out rate in 3-month intervals from the end of chemoradiation (ie, time of listing).
Figure 3
Figure 3
Kaplan–Meier curves for (A) intent-to-treat survival for the total population (N = 287); (B) recurrence-free survival for all transplanted patients (N = 214); (C) recurrence-free survival for deceased donor (N = 152) vs living donor (N = 52) liver transplantation; (D) recurrence-free survival for primary sclerosing cholangitis (N = 143) vs those without (N = 71); (E) intent-to-treat survival comparing center 1 (N = 193) vs all other centers (N = 94); and (F) recurrence-free survival comparing center 1 (N = 131) vs all other centers (N = 83). The 2-, 5-, and 10-year survival rates are shown as percentages (95% CI).
Figure 3
Figure 3
Kaplan–Meier curves for (A) intent-to-treat survival for the total population (N = 287); (B) recurrence-free survival for all transplanted patients (N = 214); (C) recurrence-free survival for deceased donor (N = 152) vs living donor (N = 52) liver transplantation; (D) recurrence-free survival for primary sclerosing cholangitis (N = 143) vs those without (N = 71); (E) intent-to-treat survival comparing center 1 (N = 193) vs all other centers (N = 94); and (F) recurrence-free survival comparing center 1 (N = 131) vs all other centers (N = 83). The 2-, 5-, and 10-year survival rates are shown as percentages (95% CI).
Figure 3
Figure 3
Kaplan–Meier curves for (A) intent-to-treat survival for the total population (N = 287); (B) recurrence-free survival for all transplanted patients (N = 214); (C) recurrence-free survival for deceased donor (N = 152) vs living donor (N = 52) liver transplantation; (D) recurrence-free survival for primary sclerosing cholangitis (N = 143) vs those without (N = 71); (E) intent-to-treat survival comparing center 1 (N = 193) vs all other centers (N = 94); and (F) recurrence-free survival comparing center 1 (N = 131) vs all other centers (N = 83). The 2-, 5-, and 10-year survival rates are shown as percentages (95% CI).
Figure 3
Figure 3
Kaplan–Meier curves for (A) intent-to-treat survival for the total population (N = 287); (B) recurrence-free survival for all transplanted patients (N = 214); (C) recurrence-free survival for deceased donor (N = 152) vs living donor (N = 52) liver transplantation; (D) recurrence-free survival for primary sclerosing cholangitis (N = 143) vs those without (N = 71); (E) intent-to-treat survival comparing center 1 (N = 193) vs all other centers (N = 94); and (F) recurrence-free survival comparing center 1 (N = 131) vs all other centers (N = 83). The 2-, 5-, and 10-year survival rates are shown as percentages (95% CI).
Figure 3
Figure 3
Kaplan–Meier curves for (A) intent-to-treat survival for the total population (N = 287); (B) recurrence-free survival for all transplanted patients (N = 214); (C) recurrence-free survival for deceased donor (N = 152) vs living donor (N = 52) liver transplantation; (D) recurrence-free survival for primary sclerosing cholangitis (N = 143) vs those without (N = 71); (E) intent-to-treat survival comparing center 1 (N = 193) vs all other centers (N = 94); and (F) recurrence-free survival comparing center 1 (N = 131) vs all other centers (N = 83). The 2-, 5-, and 10-year survival rates are shown as percentages (95% CI).
Figure 3
Figure 3
Kaplan–Meier curves for (A) intent-to-treat survival for the total population (N = 287); (B) recurrence-free survival for all transplanted patients (N = 214); (C) recurrence-free survival for deceased donor (N = 152) vs living donor (N = 52) liver transplantation; (D) recurrence-free survival for primary sclerosing cholangitis (N = 143) vs those without (N = 71); (E) intent-to-treat survival comparing center 1 (N = 193) vs all other centers (N = 94); and (F) recurrence-free survival comparing center 1 (N = 131) vs all other centers (N = 83). The 2-, 5-, and 10-year survival rates are shown as percentages (95% CI).
Figure 4
Figure 4
Kaplan–Meier recurrence-free survival curves for (A) patients who are within UNOS/OPTN criteria for standard MELD exception (N = 166) vs those who are not (N = 48); and (B) patients with a mass larger than 3 cm (N = 23) vs 3 cm or smaller (N = 191).
Figure 4
Figure 4
Kaplan–Meier recurrence-free survival curves for (A) patients who are within UNOS/OPTN criteria for standard MELD exception (N = 166) vs those who are not (N = 48); and (B) patients with a mass larger than 3 cm (N = 23) vs 3 cm or smaller (N = 191).
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