Comparative prognosis of liver transplantation versus liver resection in intrahepatic cholangiocarcinoma: a systematic review and meta-analysis

Introduction

Cholangiocarcinomas are classified based on their anatomic location as intrahepatic cholangiocarcinoma (ICC), perihilar cholangiocarcinoma (pCC), and distal cholangiocarcinoma (dCC), with pCC and dCC collectively referred to as extrahepatic cholangiocarcinoma (1,2). ICC is located proximal to the intrahepatic secondary or higher bile ducts and accounts for approximately 20% of all liver malignancies (3). The incidence of ICC is increasing globally, with significantly higher rates observed in Asian countries like South Korea, Thailand, and Japan when compared to Western countries (4-6). This rise in ICC incidence has also been accompanied by an increase in ICC-related mortality (4,7,8). The clinical manifestations of early ICC are not obvious, which makes early diagnosis still a challenge, and most patients present to the hospital with unexplained abdominal pain or jaundice, while some patients remain asymptomatic and the lesions are incidentally detected during radiologic examinations (9). Surgical resection is a widely accepted curative treatment for ICC, unfortunately, only 20–30% of patients are able to undergo this procedure (3), and postoperative recurrence rate of up to 50–60%, the 5-year survival rate following surgical resection of ICC ranges between 25% and 40% (3,10,11). Although liver resection (LR) is currently the main treatment, most patients cannot achieve hepatectomy due to factors such as portal hypertension, cirrhosis, multiple intrahepatic metastases, and vascular invasion (12). Therefore, liver transplantation (LT) may emerge as a new option. Traditionally, ICC has not been recognized and is even a contraindication to LT in most medical centers around the world because of its high recurrence rate and poor survival outcomes (13-16). During the past decade, the data of ICC patients who underwent LT mainly consisted of cases where the disease was incidentally diagnosed as ICC after the operation or misdiagnosed as hepatocellular carcinoma prior to the operation. In recent years, in order to further ascertain whether LT is an indication for ICC, LT has been permitted only in clinical studies and prospective trials. However, current research indicates that individuals with “very early” ICC—defined as a single tumor ≤2 cm in a cirrhotic liver—may benefit from early LT (17-20), on the other hand, individuals with advanced ICC considered unresectable in a noncirrhotic liver have shown relatively satisfactory transplant outcomes if the illness stabilizes following neoadjuvant treatment (21-23). Although some retrospective studies have compared the outcomes of ICC patients treated with LT and LR, a clear conclusion on the effectiveness of these treatments has not been reached. The purpose of this meta-analysis is to illustrate and carefully assess the outcomes of LT in comparison to LR for ICC patients. We present this article in accordance with the PRISMA reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-24-86/rc).

Methods

Literature search

The pertinent literature was systematically searched in PubMed, Web of Science, and the Cochrane Library spanning from 1 January 2000 to 30 April 2024. A search strategy combining subject terms and free terms was employed, with MeSH terms and search history detailed in Appendix 1. Key search terms included ‘cholangiocarcinoma’, ‘intrahepatic cholangiocarcinoma’, ‘liver transplantation’, ‘liver grafting’, ‘hepatectomy’, and ‘liver resection’. Additionally, we employed a “snowball” approach to manually search relevant references and previously published systematic reviews in order to identify potentially eligible studies that may have been overlooked.

Criteria for inclusion and exclusion

To ensure the accurate identification of all relevant records, specific criteria for inclusion and exclusion were established prior to conducting the literature search. Eligible studies had to be prospective or retrospective clinical studies comparing patients who underwent LT or LR for ICC, and providing data on 1-, 3-, 5-year overall survival rates, or recurrence-free survival rates. Only patients having an ICC diagnosis were eligible to meet the inclusion criteria, excluding those with a mixed or combined form of hepatocellular-cholangiocarcinoma. The study excluded non-English studies, reviews, in vitro or animal studies, letters to the editor, comments, studies with less than 5 patients, and original articles solely focusing on LT, resection, or other treatments, meanwhile, the studies in which the patient data were from the same database or there was an overlap in the patient data were also excluded.

Data extraction and quality assessment

Two researchers autonomously screened the literature, with any discrepancies being resolved through discussion with other colleagues. The information collected from the included studies consisted of characteristics such as the first author, year of publication, country, patient count, and the status of resection margins. The efficacy outcomes for LT and LR comprised overall survival rates or recurrence-free survival rates at 1, 3, and 5 years. The Newcastle-Ottawa Quality Scale was used to evaluate the contained literature’s quality, which serves as a primary tool for the assessment of observational studies. This scale assesses three aspects: selection of subjects, comparability between groups, and measurement of outcomes, with a maximum total score of 9 points.

Statistical analysis

Version 5.4 of the Review Manager statistics software was used to conduct the statistical analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to assess dichotomous variables. The pooled estimates for survival rates were derived using a fixed-effects model. The assessment of heterogeneity was conducted via I² statistics, with a P value of less than 0.1 and an I² value exceeding 50% indicating considerable heterogeneity. Statistical significance for the differences between the two groups was established when the P value fell below 0.05.

Results

Selection and characteristics of studies

A total of 1,263 relevant studies were found in the PubMed, Web of Science, and the Cochrane Library system, the “snowball” search method identified a study published in 1997 that also met our inclusion criteria, and we subsequently included this study in our analysis. Out of which 237 were duplicates, after excluding 191 meta-analyses, systematic reviews, reviews, case reports, and letters and excluding 716 articles because of not relevant to the research topic, 120 articles met the criteria upon reviewing the abstracts. Subsequently, 9 studies were included for qualitative synthesis and full-text reading, 2 of them used data from the Surveillance, Epidemiology, and End Results (SEER) database, while 4 of them used data from the National Cancer Database, considering the overlap in patient data, we selected 1 study from each of database to include in our analysis. Finally, 5 studies were included in our meta-analysis, and one of them was published in 1997 and was selected by reading the references (Figure 1) (24-28). All the studies were retrospective, with 1 conducted in China, 3 in the United States, and 1 in Sweden. Table 1 provides detailed information on the studies and patient characteristics.

Figure 1 The analysis’s search approach. ICC, intrahepatic cholangiocarcinoma; LR, liver resection; LT, liver transplantation.

Survival analysis

The 1-year overall survival rate

Selected research provided information on overall survival throughout various periods. Four studies evaluated 1-year overall survival, including 4,609 patients with ICC, of whom 185 underwent LT and 3,497 underwent LR. Meta-analysis results showed that the 1-year survival rate after surgery in the LT group was 83.3%, and the 1-year survival rate in the LR group was 79.7%. The survival rates between the two groups were comparable, with no statistically significant difference observed (OR: 1.42, 95% CI: 0.98–2.06, P=0.07). Furthermore, there was no heterogeneity among the included trials (P=0.79, I²=0%) (Figure 2A), the result of the meta-analysis is reported in Table 2.

Figure 2 Survival rate differences between LT and LR in the selected studies. (A) 1-year overall survival rate, (B) 3-year overall survival rate, (C) 5-year overall survival rate, (D) 1-year recurrence-free survival rate, (E) 5-year recurrence-free survival rate, (F) R0 resection rate. CI, confidence interval; LR, liver resection; LT, liver transplantation.

The 3-year overall survival rate

Four studies evaluated 3-year overall survival. These studies included 4,567 patients with ICC, of whom 212 patients underwent LT and 4,355 patients underwent LR. Meta-analysis results showed that the difference in the 3-year overall survival rate was statistically significant (OR: 1.39, 95% CI: 1.04–1.84, P=0.02), compared with LR patients, the 3-year survival rate of LT patients was slightly higher (54.2% vs. 48.4%). There was mild heterogeneity among the studies (P=0.18, I²=39%) (Figure 2B).

The 5-year overall survival rate

Four studies evaluated 5-year overall survival, including 4,609 patients with ICC, of whom 222 patients underwent LT and 4,387 underwent LR. The results of the meta-analysis indicated that the 5-year overall survival rate difference was statistically significant (OR: 1.71, 95% CI: 1.30–2.26, P<0.001). LT patients had a slightly higher 5-year survival rate than LR patients (44.6% vs. 33.1%). There was moderate heterogeneity between the trials (P=0.11, I²=51%) (Figure 2C).

The 1- and 5-year recurrence-free survival rate

Two studies evaluated 1- and 5-year recurrence-free survival rates, including 118 patients with ICC, of whom 35 underwent LT and 83 underwent LR. Meta-analysis results showed that the 1-year recurrence-free survival rate after surgery in the LT group was 71.4%, and the 1-year recurrence-free survival rate in the LR group was 69.9%. The two groups’ survival results were identical, and no statistically significant difference was found (OR: 1.36, 95% CI: 0.55–3.35, P=0.51). Furthermore, there was no heterogeneity among the included trials (P=0.36, I²=0%) (Figure 2D). Similarly, the 5-year recurrence-free survival rate after surgery in the LT group was 37.1%, and the 5-year recurrence-free survival rate in the LR group was 25.3%. The two groups’ survival results were comparable, and no statistically significant difference was found (OR: 1.85, 95% CI: 0.78–4.36, P=0.16). Also, there was no heterogeneity among the included trials (P=0.53, I²=0%) (Figure 2E).

Resection margin R0

Three studies provided data on margin status, showing an R0 resection rate of 90.0% (97/109) in the LT group and 77.7% (1,525/1,962) in the LR group. The two groups’ R0 resection rates differed significantly, according to meta-analysis. Favoring the LT group (OR: 2.39, 95% CI: 1.28–4.48, P=0.006). No heterogeneity was observed across the trials (P=0.65, I²=0%) (Figure 2F).

Subgroup analysis of studies that did not achieve R0 resection in the liver transplant group

Two studies have reported positive margins in LT for ICC, we conducted a subgroup analysis of overall survival. Meta-analysis results showed that the 1-year survival rate was 85.1% in the LT group and 82.2% in the LR group. The two groups’ survival results were identical, and no statistically significant difference was found (OR: 1.71, 95% CI: 0.91–3.21, P=0.09) (Figure 3A). Similarly, two studies assessed the overall survival rate at three years. The meta-analysis findings revealed that the overall survival rates in the two groups were comparable (46.8% vs. 49.9%), there was no statistically significant difference (OR: 1.02, 95% CI: 0.66–1.58, P=0.91) (Figure 3B). Two studies evaluated the 5-year overall survival rate, meta-analysis results showed that the 5-year survival rate after LT was 35.1%, and the LR group was 32.9%, no statistical significance was found in the difference (OR: 1.21, 95% CI: 0.77–1.89, P=0.41) (Figure 3C). From the subgroup analysis results, it can be concluded that when LT cannot achieve R0 resection for ICC, the effects of LT and LR are the same.

Figure 3 Difference of survival rates between LT and LR of the studies that did not achieve R0 resection in the liver transplant group. (A) 1-year overall survival rate, (B) 3-year overall survival rate, (C) 5-year overall survival rate. CI, confidence interval; LR, liver resection; LT, liver transplantation.

Heterogeneity and publication bias and sensitivity analysis

The 5-year overall survival rate comparing LT and LR showed moderate heterogeneity, while there was no heterogeneity in the remaining survival rate results, so pooled by the fixed effects model. As shown in the funnel plot (Figure S1), the distribution is symmetrical and the possibility of publication bias is small, indicating that the research conclusion is relatively reliable. Sensitivity analysis was performed on the included studies on a 5-year overall survival rate, after excluding one potentially heterogeneous study (28), the study results showed no significant heterogeneity (P=0.33, I²=10%), and the pooled overall effect did not change significantly.

Discussion

Surgical resection is the primary treatment for ICC. In cases of localized disease, curative resection represents the gold standard, with hepatectomy combined with neoadjuvant chemotherapy showing improved survival rates. However, the majority of patients are diagnosed with advanced-stage tumors, restricting the feasibility of curative resection to only one-third of patients (3,29,30). The inherent invasiveness of ICC contributes to multifocality, lymph node metastasis, and vascular invasion, presenting challenges in achieving complete removal of the disease with negative microscopic (R0) margins while maintaining a sufficient remnant liver volume. Consequently, long-term survival outcomes after resection are often poor, with current 5-year overall survival rates ranging from 25% to 40% (12). A retrospective analysis included 563 ICC patients who had surgical resection showing that postoperative recurrence is prevalent even after R0 resection. The study found that the 5-year recurrence rate was 73.1%, with the first recurrence site predominantly being intrahepatic (59.8%). Histologically positive margins and node involvement were identified as significant risk factors for recurrence (31). Although surgical resection is the preferred treatment for ICC, the disease is considered unresectable in cases of multiple intrahepatic tumors, distant metastases, vascular or lymph node involvement, or the presence of cirrhosis. Theoretically, LT can avoid R1 resection and insufficient residual liver volume, remove intrahepatic micro-metastases, and liver cirrhosis. Initially, ICC was considered a contraindication for LT due to lower survival rates and higher recurrence rates, the 2-year survival rate was only 30%, and overall recurrence was 36.4%, such a high recurrence rate may be unacceptable and most patients were diagnosed with ICC incidentally after surgery (15-17). Studies have shown that before 1996, the 1-year survival rate after LT ranged from 13.9% to 53% (15). After selection criteria and neoadjuvant chemo-radiation protocols were shown to be critical to improving survival in LT for ICC, the situation started to change (21,32). A study by Sapisochin et al. was the first to define the criteria for “very early” ICC and achieved very satisfactory survival results (19). “very early” ICC was defined as a single tumor with a diameter ≤2 cm, which could not be treated by LR due to cirrhosis and other reasons. In this study, eight patients belonged to the “very early” ICC group, with 1-, 3-, and 5-year survival rates of 100%, 73%, and 73%, respectively, and had no tumor recurrence, in contrast, the 1-, 3-, and 5-year survival rates were 71%, 43%, and 34% for patients in larger-tumor-size group (>2 cm in diameter), and the recurrence rate was 36.4% (19). Another larger, multicenter series was conducted by Sapisochin et al. in 2016 (18). The survival rates for 1-, 3-, and 5-year were 93%, 84%, and 65%, respectively, in the “very early” ICC group compared to 79%, 50%, and 45% in the advanced group (P=0.02). These findings are quite promising. A recent meta-analysis on the outcomes of LT for ICC revealed that the pooled overall survival rates at 1-, 3-, and 5-year were 75%, 56%, and 42%, respectively, additionally, the pooled recurrence-free survival rates at 1-, 3-, and 5-year were 70%, 49%, and 38%, respectively (20).

Patients with cirrhosis who are diagnosed with “very early” ICC or those who are carefully selected and have advanced ICC that has been treated with neoadjuvant therapy may experience significant benefits from LT (22). To demonstrate the efficacy of LT for “very early” ICC, a multicentric single-arm clinical trial (NCT02878473) is underway. Notably, patients with advanced ICC who receive neoadjuvant therapy and achieve disease stability for at least 6 months before LT may improve long-term survival outcomes. In a prospective case series, researchers evaluated the efficacy of neoadjuvant chemotherapy in patients demonstrating favorable tumor biology (21), 21 individuals with locally advanced, incurable ICC who did not have an extrahepatic illness or vascular involvement were included in the research, neoadjuvant therapy includes chemotherapy based on gemcitabine, such as gemcitabine-cisplatin (GC) or gemcitabine-capecitabine, six patients eventually met the criteria and underwent LT, the 1-, 3- and 5-year overall survival rates were 100%, 83.3%, and 83.3%, respectively, with 50% recurrence-free survival at 1-, 3-, and 5-year, these results are more promising than those previously reported with LR or LT alone without neoadjuvant therapy. This implies that LT may be advantageous for a subset of patients with locally advanced ICC who show disease stability while receiving neoadjuvant treatment. In 2010, McMillan and colleagues established a protocol for neoadjuvant therapy followed by LT specifically for unresectable ICC (24), throughout the study, 32 patients were listed as candidates for LT, and eventually, 18 of these patients successfully underwent the transplant surgery. A prerequisite for the patients to undergo LT was that they must show disease stability for 6 months while receiving neoadjuvant therapy and must not present with extrahepatic disease, despite the median cumulative tumor diameter being 10.4 cm, the observed 1-, 3-, and 5-year overall survival rates for patients who underwent LT were 100%, 71%, and 57%, respectively. These findings indicate that LT can be an effective treatment option for a highly selected group of patients with locally advanced, unresectable ICC, underscoring the potential success of this approach in improving patient outcomes. Although these studies have achieved encouraging survival results, the included cases were small, and more prospective studies are still required to determine the therapeutic value of neoadjuvant therapy combined with LT for ICC patients. A trial (NCT04195503) is now in progress to assess the effectiveness of neoadjuvant in conjunction with LT for the management of locally advanced ICC.

At present, only a few transplantation centers would perform LT for ICC when conducting clinical studies, because the efficacy of LT has been uncertain, there are few studies directly comparing LT and LR, we retrieved 5 original studies in the system, which compared the efficacy of LT and LR and reported their survival results, as shown in Table 1. This meta-analysis suggests that LT has a better long-term prognosis than LR. Specifically, LT had the same 1-year survival rate as LR, but the former showed a tendency to have better long-term outcomes over time, and this trend reached a statistical difference in the third year after surgery. LT has better 3- and 5-year survival outcomes than LR. Two original studies reported the results of the recurrence-free survival rate, and there was no statistically significant difference in the 1- and 5-year recurrence-free survival rates between the two groups. In this meta-analysis, there was a significant difference in the rate of R0 resection margin between the two groups. LT has a higher R0 resection rate, this is following the facts. Two of the included original studies reported that LT did not achieve R0 resection, according to the results of subgroup analysis, there was no difference in short-term or long-term survival between LT and LR. From a resource utilization perspective, if negative resection margins cannot be achieved even after LT, LR or systemic therapy should be considered. Due to the inherent selectivity bias in retrospective studies, it is difficult to achieve a fair comparison between groups, and in addition, randomized controlled studies between the two modalities are challenging. Meanwhile, in the comparison between LT and hepatectomy, the postoperative recurrence rate is also a crucial factor. Since none of the five original studies included in this analysis provided the results of the postoperative recurrence rate, it was impossible to compare the postoperative recurrence situations. Similarly, postoperative adjuvant chemotherapy is also an important factor influencing survival rate. Especially for patients with positive surgical margins, since the included studies did not record whether the patients underwent adjuvant chemotherapy after LT or LR, as well as the chemotherapy regimens and cycles, it was impossible to evaluate the situation of postoperative adjuvant chemotherapy for the patients. The only way to definitively compare the two surgical methods of LT and LR is through a large-sample randomized controlled trial. However, due to the current scarcity of LT resources and other reasons, it is extremely difficult to conduct such a trial at present. This is also a limitation of this study. From the analysis of the available data, LT shows promising results, but the two treatment methods have their indications, and the baseline data and tumor characteristics of the patients are not completely consistent, some of the patients who underwent LT were either misdiagnosed preoperatively with hepatocellular carcinoma (HCC) or incidentally diagnosed with ICC on explant pathology, so it is difficult to make a direct comparison. Finally, it is worth mentioning that LT is provided to patients with unresectable diseases, so LR and LT are complementary in this setting.

In addition to surgical treatment, most patients with advanced ICC must receive systemic treatment and palliative care. At present, there is an absence of chemotherapy treatments specifically tailored for patients with advanced unresectable ICC. Most chemotherapy research continues to group all forms of biliary malignancies, rather than focusing on targeted treatment options for each distinct type. Combination therapy with gemcitabine and cisplatin is the currently approved first-line treatment (33). In a phase III study conducted by Valle et al. survival outcomes were compared between patients with advanced cholangiocarcinoma treated with GC and gemcitabine alone, the survival advantage of the GC group was more obvious. Ioka et al. (34) conducted a randomized phase III trial in 39 centers showing that the addition of S-1 to GC (GCS) showed promising efficacy for advanced biliary tract cancer (BTC), 246 patients were enrolled, the 1-year overall survival rate was 59.4% in the GCS arm and 53.7% in the GC arm, the GCS regimen has shown a survival advantage and higher overall survival compared to GC in the trial, making it a potential new standard first-line chemotherapy for advanced BTC (34). Aberrant expression of key proteins [such as fibroblast growth factor receptor 2 (FGFR2) and isocitrate dehydrogenase (IDH)] in ICC has resulted in the creation of new targeted treatments (35). According to a study, approximately 70% of patients with ICC have at least one genetic change that can be taken into consideration for treatment, including FGFR2 fusions, IDH1/2, ARAF, KRAS, BRAF, and FGF19. Among these, FGFR2 fusions are the most commonly occurring targetable molecular alteration in ICC. This suggests that FGFR2 could be a promising target for therapeutic intervention in ICC patients. Mutations in IDH1 occur in as many as 25% of cholangiocarcinomas, particularly in ICC. Ivosidenib, an oral inhibitor that targets mutant IDH1 (mIDH1), showed promising outcomes in a recent phase II study in the second-line treatment (36).

A consensus document on LT for ICC was released by the International Liver Transplant Society with the intention of offering professional viewpoints, consensus, and best practices. A moderate-level conditional recommendation was provided in the report suggesting that patients with “very early” ICC may benefit from LT. Patients with noncirrhotic livers and advanced ICC who are declared unresectable may also be evaluated as LT candidates if their illness does not worsen following neoadjuvant therapy. The agreement further emphasized that, with the strongest recommendation and the greatest degree of evidence in favor, LR should be the therapy of choice for ICC. Based on moderate evidence and a strong recommendation, LT should only be used for individuals with incurable diseases under rigorous clinical trial protocols (37).

To sum up, LT has emerged as a viable therapy option for carefully chosen ICC patients; nonetheless, because organ resources are limited, LR remains the best option for patients who are suited for resection. For patients with unresectable ICC, new treatments such as systemic chemotherapy, targeted therapy, and immune therapy are widely used in clinical practice. In the future, more prospective clinical trials under strict inclusion and exclusion criteria are needed to determine the beneficiaries of LT, and more therapeutic approaches should be actively explored to improve the prognosis of ICC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-24-86/rc

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References

1. Blechacz B, Komuta M, Roskams T, et al. Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2011;8:512-22. [Crossref] [PubMed]
2. Cardinale V. Classifications and misclassification in cholangiocarcinoma. Liver Int 2019;39:260-2. [Crossref] [PubMed]
3. Moris D, Palta M, Kim C, et al. Advances in the treatment of intrahepatic cholangiocarcinoma: An overview of the current and future therapeutic landscape for clinicians. CA Cancer J Clin 2023;73:198-222. [Crossref] [PubMed]
4. Saha SK, Zhu AX, Fuchs CS, et al. Forty-Year Trends in Cholangiocarcinoma Incidence in the U.S.: Intrahepatic Disease on the Rise. Oncologist 2016;21:594-9. [Crossref] [PubMed]
5. Valle JW, Borbath I, Khan SA, et al. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27:v28-37. [Crossref] [PubMed]
6. Florio AA, Ferlay J, Znaor A, et al. Global trends in intrahepatic and extrahepatic cholangiocarcinoma incidence from 1993 to 2012. Cancer 2020;126:2666-78. [Crossref] [PubMed]
7. Vithayathil M, Khan SA. Current epidemiology of cholangiocarcinoma in Western countries. J Hepatol 2022;77:1690-8. [Crossref] [PubMed]
8. Bertuccio P, Bosetti C, Levi F, et al. A comparison of trends in mortality from primary liver cancer and intrahepatic cholangiocarcinoma in Europe. Ann Oncol 2013;24:1667-74. [Crossref] [PubMed]
9. Brown KM, Parmar AD, Geller DA. Intrahepatic cholangiocarcinoma. Surg Oncol Clin N Am 2014;23:231-46. [Crossref] [PubMed]
10. Bridgewater J, Galle PR, Khan SA, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 2014;60:1268-89. [Crossref] [PubMed]
11. Mazzaferro V, Gorgen A, Roayaie S, et al. Liver resection and transplantation for intrahepatic cholangiocarcinoma. J Hepatol 2020;72:364-77. [Crossref] [PubMed]
12. Petrowsky H, Hong JC. Current surgical management of hilar and intrahepatic cholangiocarcinoma: the role of resection and orthotopic liver transplantation. Transplant Proc 2009;41:4023-35. [Crossref] [PubMed]
13. Sapisochin G, de Lope CR, Gastaca M, et al. Intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation: a Spanish matched cohort multicenter study. Ann Surg 2014;259:944-52. [Crossref] [PubMed]
14. Becker NS, Rodriguez JA, Barshes NR, et al. Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg 2008;12:117-22. [Crossref] [PubMed]
15. Goldstein RM, Stone M, Tillery GW, et al. Is liver transplantation indicated for cholangiocarcinoma? Am J Surg 1993;166:768-71; discussion 771-2. [Crossref] [PubMed]
16. Pichlmayr R, Weimann A, Oldhafer KJ, et al. Role of liver transplantation in the treatment of unresectable liver cancer. World J Surg 1995;19:807-13. [Crossref] [PubMed]
17. Sotiropoulos GC, Kaiser GM, Lang H, et al. Liver transplantation as a primary indication for intrahepatic cholangiocarcinoma: a single-center experience. Transplant Proc 2008;40:3194-5. [Crossref] [PubMed]
18. Sapisochin G, Facciuto M, Rubbia-Brandt L, et al. Liver transplantation for "very early" intrahepatic cholangiocarcinoma: International retrospective study supporting a prospective assessment. Hepatology 2016;64:1178-88. [Crossref] [PubMed]
19. Sapisochin G, Rodríguez de Lope C, Gastaca M, et al. "Very early" intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients? Am J Transplant 2014;14:660-7. [Crossref] [PubMed]
20. Ziogas IA, Giannis D, Economopoulos KP, et al. Liver Transplantation for Intrahepatic Cholangiocarcinoma: A Meta-analysis and Meta-regression of Survival Rates. Transplantation 2021;105:2263-71. [Crossref] [PubMed]
21. Lunsford KE, Javle M, Heyne K, et al. Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: a prospective case-series. Lancet Gastroenterol Hepatol 2018;3:337-48. [Crossref] [PubMed]
22. Sapisochin G, Ivanics T, Heimbach J. Liver Transplantation for Intrahepatic Cholangiocarcinoma: Ready for Prime Time? Hepatology 2022;75:455-72. [Crossref] [PubMed]
23. McMillan RR, Javle M, Kodali S, et al. Survival following liver transplantation for locally advanced, unresectable intrahepatic cholangiocarcinoma. Am J Transplant 2022;22:823-32. [Crossref] [PubMed]
24. Huang G, Song W, Zhang Y, et al. Liver transplantation for intrahepatic cholangiocarcinoma: a propensity score-matched analysis. Sci Rep 2023;13:10630. [Crossref] [PubMed]
25. Istanbouli A, Patel S, Almerey T, et al. Surgical Treatment for Intrahepatic, Peri-Hilar, and Distal Cholangiocarcinoma: 20-Single Institutional Year Experience. Am Surg 2023;89:621-31. [Crossref] [PubMed]
26. Hue JJ, Rocha FG, Ammori JB, et al. A comparison of surgical resection and liver transplantation in the treatment of intrahepatic cholangiocarcinoma in the era of modern chemotherapy: An analysis of the National Cancer Database. J Surg Oncol 2021;123:949-56. [Crossref] [PubMed]
27. Lindnér P, Rizell M, Hafström L. The impact of changed strategies for patients with cholangiocarcinoma in this millenium. HPB Surg 2015;2015:736049. [Crossref] [PubMed]
28. Casavilla FA, Marsh JW, Iwatsuki S, et al. Hepatic resection and transplantation for peripheral cholangiocarcinoma. J Am Coll Surg 1997;185:429-36. [Crossref] [PubMed]
29. Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 2008;248:84-96. [Crossref] [PubMed]
30. Tan JC, Coburn NG, Baxter NN, et al. Surgical management of intrahepatic cholangiocarcinoma--a population-based study. Ann Surg Oncol 2008;15:600-8. [Crossref] [PubMed]
31. Spolverato G, Kim Y, Alexandrescu S, et al. Management and Outcomes of Patients with Recurrent Intrahepatic Cholangiocarcinoma Following Previous Curative-Intent Surgical Resection. Ann Surg Oncol 2016;23:235-43. [Crossref] [PubMed]
32. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693-9. [Crossref] [PubMed]
33. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-81. [Crossref] [PubMed]
34. Ioka T, Kanai M, Kobayashi S, et al. Randomized phase III study of gemcitabine, cisplatin plus S-1 versus gemcitabine, cisplatin for advanced biliary tract cancer (KHBO1401- MITSUBA). J Hepatobiliary Pancreat Sci 2023;30:102-10. [Crossref] [PubMed]
35. Vithayathil M, Bridegwater J, Khan SA. Medical therapies for intra-hepatic cholangiocarcinoma. J Hepatol 2021;75:981-3. [Crossref] [PubMed]
36. Lowery MA, Burris HA 3rd, Janku F, et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol 2019;4:711-20. [Crossref] [PubMed]
37. Sapisochin G, Javle M, Lerut J, et al. Liver Transplantation for Cholangiocarcinoma and Mixed Hepatocellular Cholangiocarcinoma: Working Group Report From the ILTS Transplant Oncology Consensus Conference. Transplantation 2020;104:1125-30. [Crossref] [PubMed]