Efficacy and safety comparison of neoadjuvant chemotherapy followed by surgery and upfront surgery for treating intrahepatic cholangiocarcinoma: a systematic review and meta-analysis
BMC Gastroenterology volume 23, Article number: 122 (2023)
Background and aims
Currently, surgical resection is the most commonly performed and effective treatment for intrahepatic cholangiocarcinoma (ICC) worldwide. However, the prognosis of ICC is unsatisfactory. This study aimed to compare the efficacy and safety of neoadjuvant chemotherapy followed by surgery and upfront surgery in treating intrahepatic cholangiocarcinoma (ICC). The study also intends to explore whether chemotherapy should be introduced before surgery and which populations should be considered for neoadjuvant chemotherapy.
Four databases, including PubMed, EMBASE, Cochrane Library, and Web of Science, were searched from their inception dates to January 2022 for relevant articles. The statistical analysis was performed using the Review Manager Software (version5.3). The non-randomized interventions (ROBINS-I) was used to assess the methodological quality of included studies and the overall quality of evidence was assessed through the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. Moreover, the primary outcomes included 1-year, 3-year and 5-year overall survival (OS), while the secondary outcomes were R0 resection, 1-year, 3-year and 5-year recurrence-free survival (RFS), postoperative complications and ninety-day postoperative mortality.
Five studies involving 2412 patients were included in this meta-analysis. There was no significant difference in 1-year OS, 3-year OS, 1-year, 3-year and 5-year RFS, postoperative complications and ninety-day postoperative mortality between the two groups. However, the meta-analysis showed that the neoadjuvant chemotherapy group had a better 5-year OS benefit in ICC patients than the upfront surgery group (OR = 1.27, 95% CI: 1.02–1.58), while the R0 resection rate was lower in neoadjuvant chemotherapy group than that in the upfront surgery group (OR = 0.49, 95% CI: 0.26–0.91).
Compared with the upfront surgery, neoadjuvant chemotherapy followed by surgery could prolong the 5-year OS without increasing the risk of postoperative complications in ICC patients. Considering that the patients in the neoadjuvant chemotherapy followed by surgery group had more advanced ICC cases, the benefits of neoadjuvant chemotherapy may be more significant in patients with more advanced ICC.
Cholangiocarcinoma is a malignant tumor originating from bile duct epithelial cells and can be divided into intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma, which can be classified into hilar and distal cholangiocarcinoma based on their anatomical location [1, 2]. ICC is the second most common liver tumor after hepatocellular carcinoma, accounting for 10% to 20% of all cholangiocarcinoma [3,4,5]. Surgical resection is the widely accepted and potentially curative therapy of choice for ICC, and the National Comprehensive Cancer Network (NCCN) guidelines recommend upfront surgery for resectable and non-metastatic ICC . However, most ICC cases are usually advanced and unresectable, with multiple intrahepatic lesions and distant metastasis due to late diagnosis . Although about 15% of ICC are resectable, the median survival is less than 3 years [4, 8]. Additionally, ICC is very prone to recurrence and metastasis after surgery, resulting in a relapse in about 22% of patients within six months after surgery , with lower 5-year overall survival (OS) (less than 40%) and 5-year recurrence-free survival (RFS) [10, 11]. Thus, ICC has a very poor prognosis.
The BILCAP phase III randomized controlled trial showed that using capecitabine as adjuvant chemotherapy following surgery can improve OS in patients with resected cholangiocarcinoma and gallbladder cancer . The trial has promoted the widespread adoption of capecitabine as a clinical practice standard for adjuvant therapy and has been included in the treatment guidelines for biliary tract cancer, including the ASCO guidelines, in various countries [13, 14]. However, the treatment has been criticized for its ability to represent the true standard of care since postoperative capecitabine therapy failed to improve OS in the intention-to-treat population, which was the primary endpoint [15, 16]. Furthermore, two other phase-III randomized clinical trials also failed to show whether adjuvant chemotherapy based on gemcitabine  or gemcitabine plus oxaliplatin  improves the OS or RFS in patients with biliary tract cancer. Therefore, it can be concluded that not all patients can benefit from adjuvant therapy, whose effectiveness is closely related to the types of chemotherapy drugs. Most importantly, most ICC are unresectable, making it impossible for the patients to undergo postoperative adjuvant chemotherapy.
In such a treatment dilemma, neoadjuvant chemotherapy, which may be used for local de-escalation and systemic control of ICC, is an appealing approach. Recently, many clinicians have reported unexpected results from neoadjuvant chemotherapy followed by surgery as the treatment for unresectable ICC; however, these studies mostly represent case reports with varying chemotherapy regimens [19,20,21,22,23,24,25,26,27,28,29]. Two studies using propensity score matching analysis showed that surgical resection had similar postoperative outcomes and survival as that of liver transplantation in patients with ICC [30, 31]. Another study showed that neoadjuvant chemotherapy and/or chemoradiation could reduce the risk of death from resectable ICC by 23% compared with upfront surgery . These results suggest that neoadjuvant chemotherapy followed by surgery could improve the prognosis of patients with ICC, especially the locally advanced ICC patients. However, there were also studies showing that negative margins (> 1 cm) rather than neoadjuvant therapy can increase the survival of patients with cholangiocarcinoma . Moreover, considering the priority treatment mode of ICC surgery, some scholars question whether the introduction of neoadjuvant chemotherapy prolongs the waiting time for surgical resection (about 6.8 months) and whether the disease will be delayed or even worsened during this period [33, 34].
With such controversies and the lack of prospective studies, a systematic review and meta-analysis could provide a better understanding of these treatment regimens using the currently available research. This study compared the neoadjuvant chemotherapy followed by surgery with upfront surgery for ICC treatment using the latest and most comprehensive studies to obtain high quality evidence to guide their clinical application.
This study was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines .
We searched PubMed, EMBASE, Cochrane Library, and Web of Science databases from their inception dates to January 2022 to obtain the relevant published articles. The search involved the use of MeSH terms and (or) free-text terms, including “Bile duct neoplasms,” “Biliary tract cancer*,” “Biliary tract cancer*,” “Cholangiocarcinoma,” “Intrahepatic cholangiocarcinoma*,” “Intrahepatic bile duct cancer,” “Neoadjuvant therapy,” “Neoadjuvant chemotherapy,” and “Preoperative chemotherapy.” The reference lists of the articles were also searched to obtain eligible related articles. The detailed search strategies of PubMed were presented in Supplementary Table 1.
Inclusion criteria and exclusion criteria for this systematic review
The inclusion criteria for the articles were: (1) the study should be comparing neoadjuvant chemotherapy followed by surgery with upfront surgery in treating ICC; (2) the study should have reported at least one outcome of interest such as RFS, OS, R0 resection rate, complications, or mortality; (3) in case of duplication, only the most detailed and complete studies were included for data extraction; (4) the study should either be randomized controlled trials or non-randomized controlled trials. Articles published only in English were included.
Studies were excluded if: (1) patients did not suffer from ICC; (2) other treatments, such as liver transplantation, were used on ICC patients; (3) they were single-arm studies or case reports; (4) they had no original data included in the manuscript.
Two reviewers (ZY and XJ) independently extracted the following data from the included studies: (1) general information including first author, publication year, country, study center, study design, interventions, sample size, and follow-up; (2) baseline patient characteristics such as age, sex, disease stage, chemotherapy regimens, RFS, OS, hospital stay duration, complications, and surgical margins; (3) results of the methodological quality evaluation and outcomes. Any disagreements were discussed and resolved by asking a third party.
Bias risk assessment and assessment of certainty of evidence
The non-randomized interventions (ROBINS-I)  was used to assess the methodological quality of included studies, including confounding factors, selection of participants into the study, classification of interventions, deviations from intended interventions, missing data, measurement of outcomes, and selection of the reported results. The quality of evidence of the included studies was classified as high, moderate, low, or very low according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) principles .
Outcomes of interest
The primary outcomes included 1-year, 3-year, and 5-year OS.
Secondary outcomes included R0 resection, 1-year, 3-year, and 5-year RFS, postoperative complications and ninety-day postoperative mortality.
A meta-analysis was performed to compare the primary and secondary outcomes of interest between neoadjuvant chemotherapy followed by surgery and upfront surgery using the Review Manager 5.3. Dichotomous and continuous variables were presented as odds ratios (OR) and mean difference (MD), respectively, with a 95% confidence interval (CI). Moreover, the Mantel–Haenszel (MH) and inverse-variance (IV) methods were applied for dichotomous and continuous variables, respectively. Heterogeneity was assessed through the Chi-square (χ2) and heterogeneity (I2) test statistics, of which the latter could be divided into low (I2 < 25%), moderate (25 > I2 < 50%), and high heterogeneity (I2 > 50%) . We used the fixed-effect model when the I2 value was < 50%; otherwise, a random-effects model was applied. The statistical significance of the p < 0.05 value was determined using the Z test. However, publication bias analysis was not performed because we included fewer studies (less than 10).
We initially identified 3935 potentially relevant studies and retained 3089 for screening after removing the duplicated studies. Among these, 3003 studies were excluded after the title and abstract screening, and full text of 86 studies was read. We subsequently excluded 81 studies including 3 studies [39,40,41] that explored the effects of concurrent chemoradiotherapy in patients with biliary tract cancer and 1 study  did not provide sufficient original data in the manuscript on patients with advanced-stage. Eventually, 5 studies with 2412 patients were included in this meta-analysis. Of these, two studies were conducted in the USA [32, 43], two in France [44, 45], and one in the multicenter . The PRISMA flow chart of the systematic literature search is presented in Fig. 1.
Study characteristics and quality assessment
The baseline characteristics and types of all included studies are shown in Table 1. Among the 2412 patients included in the meta-analysis, 640 were under the neoadjuvant chemotherapy followed by surgery group, while 1772 were under the upfront surgery group. The characteristics and general information of all included studies are summarized in Table 1.
Two studies [32, 46] were classified as having a serious risk of bias, and the other three studies [43,44,45] were classified as having a moderate risk of bias. All of the above assessments were based on 5-year OS, the assessments based on all outcomes were shown in Table 2, and the quality of evidence of the included studies was shown in Table 3.
Four studies [43,44,45,46] reported 1-year OS of the two procedures, and a fixed effects model was used for the analysis because no significant heterogeneity was observed between the studies (2 = 1.66, P = 0.56, I2 = 0). We found no significant differences between the two groups (OR = 0.94, 95% CI: 0.59–1.50) (Fig. 2).
Similarly, four studies [43,44,45,46] reported 3-year OS of the two procedures, and a fixed effects model was used for the analysis (2 = 2.79, P = 0.43, I2 = 0), which revealed that there was no significant difference between the two groups (OR = 1.17, 95% CI: 0.80–1.72) (Fig. 3).
All studies reported 5-year OS of the two procedures, and the meta-analysis revealed a statistically significant difference between the two groups (OR = 1.27, 95% CI: 1.02–1.58), with a moderate heterogeneity (2 = 7.54, P = 0.11, I2 = 47%) (Fig. 4).
Four studies [32, 44,45,46] reported R0 resection of the two procedures. We used a random effects model for the analysis because a high heterogeneity was observed between the studies (2 = 11.99, P = 0.007, I2 = 75%). The meta-analysis also showed a significant difference between the two groups (OR = 0.49, 95% CI: 0.26–0.91) (Table 4).
One-year RFS of the two procedures was reported by four studies [43,44,45,46]. The meta-analysis revealed no significant heterogeneity (2 = 2.88, P = 0.41, I2 = 0%) and difference (OR = 0.95, 95% CI: 0.64–1.40) between the two groups (Table 4).
Three-year RFS of the two procedures was also reported by four studies [43,44,45,46], and no significant difference between the two groups (OR = 1.02, 95% CI: 0.68–1.52) and heterogeneity (2 = 1.32, P = 0.72, I2 = 0%) between the studies was observed (Table 4).
Three studies [44,45,46] reported 5-year RFS of the two procedures, and our meta-analysis revealed no statistically significant difference between the two groups (OR = 0.89, 95% CI: 0.57–1.39) and heterogeneity between the studies (2 = 0.71, P = 0.70, I2 = 0) (Table 4).
Four studies [43,44,45,46] reported postoperative complications (Clavien-Dindo Grade ≥ III) of the two procedures, and the data from three studies [44,45,46] can be used for quantitative analysis. We used a random effects model for the analysis because a high heterogeneity was observed between the studies (2 = 6.00, P = 0.05, I2 = 67%). The meta-analysis showed there was no significant difference between the two groups (OR = 1.23, 95% CI: 0.51–2.97) (Table 4).
Ninety-day postoperative mortality
The ninety-day postoperative mortality of the two procedures was reported by three studies [44,45,46]. The meta-analysis revealed no statistically significant difference between the two groups (OR = 0.76, 95% CI: 0.28–2.01) and heterogeneity among the studies (2 = 0.54, P = 0.76, I2 = 0) (Table 4).
Sensitivity analysis of the primary outcomes (1-year, 3-year, and 5-year OS, and R0 resection) and secondary outcomes (1-year, 3-year, and 5-year RFS, postoperative complications, and ninety-day postoperative mortality) was performed by removing one study at a time from the meta-analysis using the Review Manager 5.3 and testing their heterogeneity differences. The results indicated that, for R0 resection, the heterogeneity reduced significantly when the study by Mason et al.  was excluded (2 = 0.18, P = 0.92, I2 = 0); however, the recalculated results were consistent with those obtained when all studies were included. For postoperative complications, when the study by Buettner et al.  was excluded, the heterogeneity reduced significantly (χ2 = 0.32, P = 0.57, I2 = 0) while the recalculated results were consistent with those obtained when all studies were included (OR 0.74, 95% CI 0.35–1.55). However, the recalculated results showed that the postoperative complications in the upfront surgery group was fewer than the neoadjuvant chemotherapy followed by surgery group (OR 1.95, 95% CI 1.07–3.58) and the heterogeneity decreased (χ2 = 1.13, P = 0.29, I2 = 12%) when the study by Le Roy et al.  was excluded. No significant change was found in the overall statistical significance of the model.
Although the use of neoadjuvant chemotherapy in ICC treatment is still in the exploratory stage, its application in managing other cancer types has increased with promising results . This is mainly due to the rarity of ICC, making randomized controlled trials and large prospective studies impractical . Moreover, the lack of high-level evidence and the concerns about the toxic preoperative effects of chemotherapy drugs limit the use of neoadjuvant chemotherapy for ICC treatment. The delayed diagnosis, strong invasiveness and poor prognosis of ICC also make the existing treatment options insufficient, necessitating urgent development of effective interventions. Studies have shown that neoadjuvant chemotherapy is mainly used in ICC to downstage locally advanced tumors, improve R0 resection rate, prioritize or increase receipt of systemic treatment, and enhance patient selection for major surgery, thus, facilitating an in vivo effectiveness test of the treatment . Therefore, it is important to determine whether neoadjuvant chemotherapy, particularly neoadjuvant chemotherapy followed by surgery, has an oncological advantage, such as survival benefits, to patients with ICC. If neoadjuvant therapy can only benefit some patients based on the individualized characteristics of the tumors, identifying such patients will greatly facilitate the future advancement and refinement of the treatment.
Our study found that the R0 resection rate was significantly lower in the neoadjuvant chemotherapy group than in the upfront surgery group. This may be due to the selection bias that patients in the neoadjuvant chemotherapy group were more likely to have more advanced or initially unresectable ICC across the five studies included in this analysis, while those in the upfront surgery group were resectable. This is also a common problem in non-randomized controlled trials, and although the authors tried to minimize the bias using propensity score matching analysis, it is difficult to eliminate the bias based on the current clinical criteria for choosing neoadjuvant chemotherapy for treating ICC [32, 46]. Previous studies have shown that R0 resection is an independent risk factor affecting the ICC prognosis in local control and long-term survival and is one of the outcomes pursued by surgeons [33, 39, 48]. However, although the short-term OS (1-year and 3-year OS) was not statistically different between the two groups, the 5-year OS was remarkably higher in the neoadjuvant chemotherapy group than in the upfront surgery group. A possible explanation could be that the introduction of neoadjuvant chemotherapy made the prognostic impact of R0 resection less important. That is, the positive prognostic impact of neoadjuvant chemotherapy outweighed the negative impact of R1 or R2 resection, consistent with our previous understanding of the vital role of R0 resection in malignancies treatment. Another possible explanation is that applying postoperative adjuvant chemotherapy and re-intervention when ICC recurs was not balanced between the two groups. Moreover, the overall postoperative adjuvant therapy is not widely used, and no quantitative comparison of ICC relapse re-intervention was found in the five studies. The large disparity in the number of patients between the two groups may have also contributed to the statistical Type I errors .
We also noted that the OS benefit of the neoadjuvant chemotherapy was only manifested on a long-term basis, which may be attributed to the tumor factors and recurrence pattern of ICC. Similarly, studies have shown no survival advantage when all ICC patients (stages I-III) are considered but recorded statistically significant differences in their five-year OS or median OS when only stage II-III patients were considered for analysis [6, 42]. Additionally, Marcus et al.  also found that for patients with more advanced disease, the receipt of neoadjuvant chemotherapy was associated with significantly improved survival compared to upfront surgery (Stage II, P = 0.040; Stage III, P = 0.003),while there was no statistically significant difference between the two treatment strategies in patients with clinical stage I (P = 0. 30). Thus, it could be inferred that neoadjuvant chemotherapy has better effects on patients with more advanced stage ICC, which are the most important stages in clinical practice. This is consistent with our finding that the neoadjuvant chemotherapy group had higher 5-year OS than the upfront surgery group despite the former having advanced-stage ICC participants. Sutton et al. also found that neoadjuvant chemotherapy was independently associated with improved 5-year OS when evaluating tumor stage management using multivariate analysis .
Although studies have shown that neoadjuvant therapy is an independent predictor of RFS , no statistical differences in short-term and long-term RFS were found between the two groups. This may be attributed to the high and early recurrence of ICC, which could not be inhibited by the neoadjuvant chemotherapy followed by surgery. Hu et al. retrospectively analyzed the recurrence patterns and timing of ICC after a curative-intent resection in 920 patients . The study found that 66% of the patients experienced recurrence within a median follow-up in 38 months, with pure intrahepatic recurrence being the most common at 53.2%. Other studies also reported similar results showing that the most common recurrence site was the liver [9, 43,44,45]. Furthermore, in the event of recurrence, repeated surgical resection leads to better survival than other treatments . Thus, the small number of patients included in the neoadjuvant chemotherapy group may have resulted in the absence of statistical significance in the difference between the RFS in this study. Large-sampled and high-quality studies are, therefore, needed to further validate and explore this phenomenon.
Clearly, not all patients with ICC could benefit from neoadjuvant therapy in terms of OS and RFS, especially the latter. This might have been due to the external confounding factor, which was the differences in the chemotherapy regimens used in the included studies, especially the choice of chemotherapy drugs. Two classic randomized controlled trials, ABC-02 and BT22, have demonstrated the efficacy and safety of cisplatin and gemcitabine in treating advanced biliary tract cancer . Therefore, the neoadjuvant chemotherapy drugs in this study are mostly based on gemcitabine, and according to multiple case reports, gemcitabine administration seems like a very promising treatment in combination with other neoadjuvant chemotherapy drugs. However, there is no consensus on the choice of single or multiple agents in the neoadjuvant chemotherapy for ICC, and the dosage and chemotherapy cycle also vary widely among these reported studies. Although studies have shown no difference in the impact of single-drug or multi-drug treatment on the survival benefit of ICC patients [32, 54], clinicians seem to be more willing to try multiple agents therapy during neoadjuvant chemotherapy in ICC. Therefore, this necessitates a unified neoadjuvant chemotherapy regimen. Furthermore, the internal confounding factors are the individual differences among patients, such as tumor stage and genes, which may influence the patient’s response to neoadjuvant chemotherapy. Early identification of the patients potentially benefiting from neoadjuvant chemotherapy or prognosis prediction of the ICC patients may aid in providing personalized medical interventions. Accordingly, research on predictive models or tools has yielded initial results in this area [55,56,57,58,59,60].
With respect to safety, no statistical difference in severe postoperative complications [44, 61] and ninety-day postoperative mortality was found between the neoadjuvant chemotherapy followed by surgery and upfront surgery groups. Our findings are consistent with a study of Choi et al.  that based on the ACS-NSQIP database. In our study, four [43,44,45,46] studies reported Clavien-Dindo Grade ≥ III complications associated with the treatment, of which, one study  providing qualitative descriptions that neoadjuvant chemotherapy was not associated with Clavien-Dindo Grade ≥ III complications. The ninety-day postoperative mortality is an important outcome that is influenced by factors such as preoperative treatment, surgical quality, patients, surgeons, and medical institutions, and is a legitimate parameter that measures the safety of treatment procedures [63, 64]. Although these data are insufficient for evaluating the safety of neoadjuvant chemotherapy followed by surgery, the intraoperative, short-term and long-term complications after neoadjuvant chemotherapy need further studies.
In general, using neoadjuvant chemotherapy followed by surgery for treating ICC requires robust data for experimental evidence; however, this is limited by the lack of randomized controlled trials and the difficulty in developing large-scale studies. This study conducted a meta-analysis of the efficacy and safety of neoadjuvant chemotherapy using relevant articles published in recent years, and preliminary conclusions were drawn. The study also reviewed the results of the previous related studies. Despite all the findings, this study also has several limitations. First, we only included a few retrospective studies with fewer patients in the neoadjuvant chemotherapy group than in the upfront surgery group, which limits the quality of the study. Secondly, there were differences in the chemotherapy regimens used in the included studies, especially in selecting chemotherapy drugs, which is critical for studies involving drugs. Thirdly, the patients in the neoadjuvant group had more advanced ICC cases, resulting in a selection bias of patients because the bias could not be eliminated. Finally, the included studies reported very few short- and long-term complications necessary for detailed safety assessment of aspect treatments.
Compared with the upfront surgery, neoadjuvant chemotherapy followed by surgery exhibited no significant RFS benefit, but it could prolong the 5-year OS of the ICC patients without increasing the risk of postoperative complications. Thus, neoadjuvant chemotherapy followed by surgery should be considered in ICC, especially in patients with more advanced disease.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and its supplementary information files.
Jarnagin WR. Biliary tract: Is there a role for neoadjuvant and adjuvant therapy in biliary cancer? Nat Rev Gastroenterol Hepatol. 2012;9(11):622–3.
Kingham TP, Aveson VG, Wei AC, Castellanos JA, Allen PJ, Nussbaum DP, Hu Y, D’Angelica MI. Surgical management of biliary malignancy. Curr Probl Surg. 2021;58(2):100854.
Zori AG, Yang D, Draganov PV, Cabrera R. Advances in the management of cholangiocarcinoma. World J Hepatol. 2021;13(9):1003–18.
Buettner S, van Vugt JL, IJzermans JN, Groot Koerkamp B. Intrahepatic cholangiocarcinoma: current perspectives. Onco Targets Ther. 2017;10:1131–42.
Lauterio A, De Carlis R, Centonze L, Buscemi V, Incarbone N, Vella I, De Carlis L. Current Surgical Management of Peri-Hilar and Intra-Hepatic Cholangiocarcinoma. Cancers (Basel). 2021;13(15):3657.
Cools KS, Glazer ES. A Tool for Patient-Focused Care Regarding Neoadjuvant Chemotherapy for Intrahepatic Cholangiocarcinoma. Ann Surg Oncol. 2021;28(4):1874–5.
Akateh C, Ejaz AM, Pawlik TM, Cloyd JM. Neoadjuvant treatment strategies for intrahepatic cholangiocarcinoma. World J Hepatol. 2020;12(10):693–708.
Amini N, Ejaz A, Spolverato G, Kim Y, Herman JM, Pawlik TM. Temporal trends in liver-directed therapy of patients with intrahepatic cholangiocarcinoma in the United States: a population-based analysis. J Surg Oncol. 2014;110(2):163–70.
Ercolani G, Vetrone G, Grazi GL, Aramaki O, Cescon M, Ravaioli M, Serra C, Brandi G, Pinna AD. Intrahepatic cholangiocarcinoma: primary liver resection and aggressive multimodal treatment of recurrence significantly prolong survival. Ann Surg. 2010;252(1):107–14.
Chan KM, Tsai CY, Yeh CN, Yeh TS, Lee WC, Jan YY, Chen MF. Characterization of intrahepatic cholangiocarcinoma after curative resection: outcome, prognostic factor, and recurrence. BMC Gastroenterol. 2018;18(1):180.
Zhang H, Yang T, Wu M, Shen F. Intrahepatic cholangiocarcinoma: Epidemiology, risk factors, diagnosis and surgical management. Cancer Lett. 2016;379(2):198–205.
Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20(5):663–73.
Liang HJ, Qin SK, Shen F, Bi F, Qin LX, Dai GH, Li EX, Liu XF, Gu YH, Yin BB, et al. Expert Consensus on Diagnosis and Treatment of CSCO Biliary System Tumors (2019 Edition). Chin Clin Oncol. 2019;24:828–38.
Shroff RT, Kennedy EB, Bachini M, Bekaii-Saab T, Crane C, Edeline J, El-Khoueiry A, Feng M, Katz MHG, Primrose J, Soares HP, et al. Adjuvant Therapy for Resected Biliary Tract Cancer: ASCO Clinical Practice Guideline. J Clin Oncol. 2019;37(12):1015–27.
Rizzo A, Brandi G. BILCAP trial and adjuvant capecitabine in resectable biliary tract cancer: reflections on a standard of care. Expert Rev Gastroenterol Hepatol. 2021;15(5):483–5.
Lamarca A, Edeline J, McNamara MG, Hubner RA, Nagino M, Bridgewater J, Primrose J, Valle JW. Current standards and future perspectives in adjuvant treatment for biliary tract cancers. Cancer Treat Rev. 2020;84:101936.
Ebata T, Hirano S, Konishi M, Uesaka K, Tsuchiya Y, Ohtsuka M, Kaneoka Y, Yamamoto M, Ambo Y, Shimizu Y, et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018;105(3):192–202.
Edeline J, Benabdelghani M, Bertaut A, Watelet J, Hammel P, Joly JP, Boudjema K, Fartoux L, Bouhier-Leporrier K, Jouve JL, et al. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J Clin Oncol. 2019;37(8):658–67.
Fujiwara Y, Ioka T, Matsui H, Tokumitsu Y, Shindo Y, Matsukuma S, Nakajima M, Yamada K, Watanabe Y, Tomochika S, et al. A Case of Intrahepatic Cholangiocarcinoma in the Elderly Patient with Curative Resection after Neoadjuvant Chemotherapy. Gan To Kagaku Ryoho. 2021;48(13):2085–7.
Otani T, Sakata J, Kameyama H, Otani A, Hirose Y, Tamura H, Morimoto Y, Miura K, Yoshino K, Kido T, et al. Surgical Resection after Gemcitabine plus Cisplatin Chemotherapy for Intrahepatic Cholangiocarcinoma with Multiple Lymph Node Metastases - Report of a Case. Gan To Kagaku Ryoho. 2016;43(12):1764–6.
Kamo N, Mori A, Nitta T, Hatano E, Mitsuyoshi H, Ikeda K, Uemoto S. Two cases of curatively resected intrahepatic cholangiocellular carcinomas through effective response to neoadjuvant chemotherapy. Gan To Kagaku Ryoho. 2011;38(2):305–8.
Higashiguchi M, Yamada D, Akita H, Eguchi H, Iwagami Y, Asaoka T, Noda T, Gotoh K, Kobayashi S, Sakai D, et al. Successful R0 Resection of Hilar Cholangiocarcinoma by Extrahepatic Bile Duct Resection Due to Accompanying Liver Dysfunction after Neoadjuvant Gemcitabine/Cisplatin/S-1 Combination Chemotherapy-A Case Report. Gan To Kagaku Ryoho. 2019;46(2):342–4.
Kuga Y, Moriya T, Fukuda S, Nishida T. Resection of Advanced Intrahepatic Cholangiocarcinoma after an Effective Response to S-1 and Gemcitabine Combination Therapy. Gan To Kagaku Ryoho. 2016;43(6):773–5.
Tada S, Fujikawa T, Tanaka A, Abe T, Yoshimoto Y, Maekawa H, Shimoike N, Tanaka H, Kawashima T, Shiraishi K. A case of unresectable hilar cholangiocarcinoma successfully treated by gemcitabine and S-1 combination chemotherapy. Gan To Kagaku Ryoho. 2012;39(8):1279–82.
Shirasaki K, Morikawa T, Otsuka H, Katayose Y, Unno M. A long term survival case of hilar cholangiocarcinoma with multiple metastases treated with chemotherapy and operation. Gan To Kagaku Ryoho. 2014;41(12):1530–2.
Kawashima H, Takeda Y, Nakahira S, Mukai Y, Hamanaka M, Uchiyama C, Kanemura T, Okishiro M, Takeno A, Suzuki R, et al. A case of advanced cholangiolocellular carcinoma successfully treated by neoadjuvant chemotherapy with gemcitabine followed by radical resection. Gan To Kagaku Ryoho. 2012;39(12):2113–5.
Hashimoto K, Tono T, Nishida K, Nonaka R, Tsunashima R, Fujie Y, Fujita S, Fujita J, Yoshida T, Ohnishi T, et al. A case of curatively resected advanced intrahepatic cholangiocellular carcinoma through effective response to neoadjuvant chemotherapy. Gan To Kagaku Ryoho. 2014;41(12):2083–5.
Kanomata H, Seyama Y, Tani K, Tanizawa T, Warabi M, Murayama M, Asano T, Takahashi M, Matsuoka Y, Miyamoto Y, et al. Long Term Survival in a Case of Hilar Cholangiocarcinoma Treated with Chemotherapy and Surgery. Gan To Kagaku Ryoho. 2015;42(12):1479–81.
Wu JH, Zhou DE, Yu YQ, Li BZ, Lu LJ, Liu DR, Wang L, Peng SY, Li JT. Surgical resection of intrahepatic cholangiocarcinoma after neoadjuvant chemotherapy: a case report and literature review. Chin J Pract Surg. 2017;37:818–20+822.
Hue JJ, Rocha FG, Ammori JB, Hardacre JM, Rothermel LD, Chavin KD, Winter JM, Ocuin LM. 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(4):949–56.
Kim P, Littau M, Baker TB, Abdelsattar Z, Tonelli C, Bunn C, Kulshrestha S, Luchette FA, Baker MS. Intrahepatic cholangiocarcinoma: Is there a role for liver transplantation? Surgery. 2022;171(3):741–6.
Mason MC, Massarweh NN, Tzeng CD, Chiang YJ, Chun YS, Aloia TA, Javle M, Vauthey JN, Tran Cao HS. Time to Rethink Upfront Surgery for Resectable Intrahepatic Cholangiocarcinoma? Implications from the Neoadjuvant Experience. Ann Surg Oncol. 2021;28(11):6725–35.
Glazer ES, Liu P, Abdalla EK, Vauthey JN, Curley SA. Neither neoadjuvant nor adjuvant therapy increases survival after biliary tract cancer resection with wide negative margins. J Gastrointest Surg. 2012;16(9):1666–71.
Le VH, O’Connor VV, Li D, Melstrom LG, Fong Y, DiFronzo AL. Outcomes of neoadjuvant therapy for cholangiocarcinoma: A review of existing evidence assessing treatment response and R0 resection rate. J Surg Oncol. 2021;123(1):164–71.
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, Henry D, Altman DG, Ansari MT, Boutron I, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919.
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henry D, et al. Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.
Jung JH, Lee HJ, Lee HS, Jo JH, Cho IR, Chung MJ, Park JY, Park SW, Song SY, Bang S. Benefit of neoadjuvant concurrent chemoradiotherapy for locally advanced perihilar cholangiocarcinoma. World J Gastroenterol. 2017;23(18):3301–8.
Kobayashi S, Tomokuni A, Gotoh K, Takahashi H, Akita H, Marubashi S, Yamada T, Teshima T, Fukui K, Fujiwara Y, et al. A retrospective analysis of the clinical effects of neoadjuvant combination therapy with full-dose gemcitabine and radiation therapy in patients with biliary tract cancer. Eur J Surg Oncol. 2017;43(4):763–71.
Fareed MM, DeMora L, Esnaola NF, Denlinger CS, Karachristos A, Ross EE, Hoffman J, Meyer JE. Concurrent chemoradiation for resected gall bladder cancers and cholangiocarcinomas. J Gastrointest Oncol. 2018;9(4):762–8.
Utuama O, Permuth JB, Dagne G, Sanchez-Anguiano A, Alman A, Kumar A, Denbo J, Kim R, Fleming JB, Anaya DA. Neoadjuvant Chemotherapy for Intrahepatic Cholangiocarcinoma: A Propensity Score Survival Analysis Supporting Use in Patients with High-Risk Disease. Ann Surg Oncol. 2021;28(4):1939–49.
Sutton TL, Billingsley KG, Walker BS, Enestvedt CK, Dewey EN, Orloff SL, Mayo SC. Neoadjuvant chemotherapy is associated with improved survival in patients undergoing hepatic resection for intrahepatic cholangiocarcinoma. Am J Surg. 2021;221(6):1182–7.
Le Roy B, Gelli M, Pittau G, Allard MA, Pereira B, Serji B, Vibert E, Castaing D, Adam R, Cherqui D, et al. Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma. Br J Surg. 2018;105(7):839–47.
Riby D, Mazzotta AD, Bergeat D, Verdure L, Sulpice L, Bourien H, Lièvre A, Rolland Y, Garin E, Boudjema K, et al. Downstaging with Radioembolization or Chemotherapy for Initially Unresectable Intrahepatic Cholangiocarcinoma. Ann Surg Oncol. 2020;27(10):3729–37.
Buettner S, Koerkamp BG, Ejaz A, Buisman FE, Kim Y, Margonis GA, Alexandrescu S, Marques HP, Lamelas J, Aldrighetti L, et al. The effect of preoperative chemotherapy treatment in surgically treated intrahepatic cholangiocarcinoma patients-A multi-institutional analysis. J Surg Oncol. 2017;115(3):312–8.
van Roessel S, Soer EC, Daamen LA, van Dalen D, FariñaSarasqueta A, Stommel MWJ, Molenaar IQ, van Santvoort HC, van de Vlasakker VCJ, de Hingh IHJT, et al. Preoperative misdiagnosis of pancreatic and periampullary cancer in patients undergoing pancreatoduodenectomy: A multicentre retrospective cohort study. Eur J Surg Oncol. 2021;47(10):2525–32.
Kuboki S, Yoshitomi H, Furukawa K, Takayashiki T, Takano S, Miyazaki M, Ohtsuka M. Multidisciplinary treatment combined with neoadjuvant downsizing chemotherapy and aggressive regional lymph node dissection to achieve r0 resection improves prognosis in patients with advanced intrahepatic cholangiocarcinoma. HPB. 2018;Supplement 2:S183.
Akobeng AK. Understanding type I and type II errors, statistical power and sample size. Acta Paediatr. 2016;105(6):605–9.
Marcus R, Christopher W, Keller J, Nassoiy S, Chang SC, Goldfarb M, Wolf R, Jutric Z. Systemic Therapy Is Associated with Improved Oncologic Outcomes in Resectable Stage II/III Intrahepatic Cholangiocarcinoma: An Examination of the National Cancer Database over the Past Decade. Cancers (Basel). 2022;14(17):4320.
Lang H, Baumgart J, Heinrich S, Huber T, Heuft LK, Margies R, Mittler J, Hahn F, Gerber TS, Foerster F, et al. Liver Resection for Intrahepatic Cholangiocarcinoma-Single-Center Experience with 286 Patients Undergoing Surgical Exploration over a Thirteen Year Period. J Clin Med. 2021;10(16):3559.
Hu LS, Zhang XF, Weiss M, Popescu I, Marques HP, Aldrighetti L, Maithel SK, Pulitano C, Bauer TW, Shen F, et al. Recurrence Patterns and Timing Courses Following Curative-Intent Resection for Intrahepatic Cholangiocarcinoma. Ann Surg Oncol. 2019;26(8):2549–57.
Valle JW, Furuse J, Jitlal M, Beare S, Mizuno N, Wasan H, Bridgewater J, Okusaka T. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann Oncol. 2014;25(2):391–8.
Azab B, Macedo FI, Ripat C, Hoefer R, Guye M, Livingstone AS, Yakoub D. The impact of neoadjuvant therapy vs. upfront surgery on margin-negative resection rate and overall survival among intrahepatic cholangiocarcinoma patients. HPB. 2019;21 Supplement 1:S18–9.
Tsilimigras DI, Mehta R, Moris D, Sahara K, Bagante F, Paredes AZ, Moro A, Guglielmi A, Aldrighetti L, Weiss M, et al. A Machine-Based Approach to Preoperatively Identify Patients with the Most and Least Benefit Associated with Resection for Intrahepatic Cholangiocarcinoma: An International Multi-institutional Analysis of 1146 Patients. Ann Surg Oncol. 2020;27(4):1110–9.
Tsilimigras DI, Hyer JM, Paredes AZ, Diaz A, Moris D, Guglielmi A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, et al. A Novel Classification of Intrahepatic Cholangiocarcinoma Phenotypes Using Machine Learning Techniques: An International Multi-Institutional Analysis. Ann Surg Oncol. 2020;27(13):5224–32.
Tsilimigras DI, Sahara K, Wu L, Moris D, Bagante F, Guglielmi A, Aldrighetti L, Weiss M, Bauer TW, Alexandrescu S, et al. Very Early Recurrence After Liver Resection for Intrahepatic Cholangiocarcinoma: Considering Alternative Treatment Approaches. JAMA Surg. 2020;155(9):823–31.
Grenader T, Nash S, Plotkin Y, Furuse J, Mizuno N, Okusaka T, Wasan H, Valle J, Bridgewater J. Derived neutrophil lymphocyte ratio may predict benefit from cisplatin in the advanced biliary cancer: the ABC-02 and BT-22 studies. Ann Oncol. 2015;26(9):1910–6.
Omichi K, Cloyd JM, Yamashita S, Tzeng CD, Conrad C, Chun YS, Aloia TA, Vauthey JN. Neutrophil-to-lymphocyte ratio predicts prognosis after neoadjuvant chemotherapy and resection of intrahepatic cholangiocarcinoma. Surgery. 2017;162(4):752–65.
Bridgewater J, Lopes A, Wasan H, Malka D, Jensen L, Okusaka T, Knox J, Wagner D, Cunningham D, Shannon J, et al. Prognostic factors for progression-free and overall survival in advanced biliary tract cancer. Ann Oncol. 2016;27(1):134–40.
Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205–13.
Choi WJ, Ivanics T, Claasen MPAW, Gallinger S, Hansen B, Sapisochin G. Is it safe to administer neoadjuvant chemotherapy to patients undergoing hepatectomy for intrahepatic cholangiocarcinoma? ACS-NSQIP propensity-matched analysis. HPB (Oxford). 2022;24(9):1535–42.
Taylor M, Grant SW, West D, Shackcloth M, Woolley S, Naidu B, Shah R. Ninety-Day Mortality: Redefining the Perioperative Period After Lung Resection. Clin Lung Cancer. 2021;22(4):e642–5.
Mise Y, Vauthey JN, Zimmitti G, Parker NH, Conrad C, Aloia TA, Lee JE, Fleming JB, Katz MH. Ninety-day Postoperative Mortality Is a Legitimate Measure of Hepatopancreatobiliary Surgical Quality. Ann Surg. 2015;262(6):1071–8.
We want to thank the institution, China Evidence-based Medicine Center, West China Hospital, Sichuan University, for their assistance throughout the development of our study.
There was no funding support for this work.
Ethics approval and consent to participate
Consent for publication
All authors agreed to publish.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Yang, Z., Jiang, X. Efficacy and safety comparison of neoadjuvant chemotherapy followed by surgery and upfront surgery for treating intrahepatic cholangiocarcinoma: a systematic review and meta-analysis. BMC Gastroenterol 23, 122 (2023). https://doi.org/10.1186/s12876-023-02754-y
- Intrahepatic cholangiocarcinoma
- Neoadjuvant chemotherapy
- Upfront surgery