Abstract
Background:
Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy with a poor prognosis. Radical resection is the modality to cure patients with ICC. Thus, surgical quality is the key prognostic factor for survival. Textbook outcome (TO) is a multidimensional composite indicator reflecting surgical care quality. However, the association between neoadjuvant therapies—particularly those incorporating targeted and/or immunotherapeutic agents into chemotherapy regimens—and the attainment of TO in ICC remains unclear and warrants further investigation.
Materials and methods:
This retrospective study analyzed 187 patients with ICC who underwent curative resection. TO was defined as the simultaneous achievement of R0 resection, with no perioperative blood transfusion, no postoperative complications, no mortality within 30 days, no unplanned readmission within 30 days, and a postoperative length of stay not exceeding the 75th percentile. Logistic regression was used to identify factors associated with TO, with further analysis focused on the role of neoadjuvant therapy. Cox regression was used to evaluate prognostic factors for overall survival (OS), and a prognostic nomogram incorporating TO was developed and validated.
Results:
TO was achieved in 53 patients (28.3%), which was significantly associated with improved OS (p = 0.003) and recurrence-free survival (p < 0.001). Multivariable analysis identified neoadjuvant therapy [odds ratio (OR) = 2.687, p = 0.014], higher body mass index, higher albumin levels, lower carcinoembryonic antigen levels, and reduced blood loss as independent predictors of TO. Combination neoadjuvant regimens (chemotherapy plus targeted/immunotherapy; OR = 2.647, p = 0.009) were the primary contributors to this positive association. A nomogram integrating TO, lymph node metastasis, prothrombin time, and adjuvant therapy demonstrated excellent predictive accuracy for survival (1-year area under the curve = 0.891).
Conclusion:
Achieving TO is associated with significantly improved survival in patients with ICC. Combined neoadjuvant therapy, including targeted or immunotherapy, is an independent positive predictor of TO, which challenges conventional perspectives. The proposed TO-integrated nomogram is a practical tool for prognostic prediction and surgical quality assessment.
Introduction
Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor that originates from the intrahepatic biliary epithelium, accounting for approximately 10%–20% of all cholangiocarcinoma cases. It is the second most common primary liver malignancy, constituting approximately 10% of all primary liver cancers (1, 2). The global incidence of ICC has been significantly increasing in recent years (3). The disease is highly aggressive and associated with a poor prognosis, with postoperative 3- and 5-year overall survival (OS) rates of only 30% and 18%, respectively (4). Complete surgical resection remains the primary curative treatment for ICC (5); however, only approximately 30% of patients are considered eligible for resection at initial diagnosis (6). Recent advances in neoadjuvant therapy, including chemotherapy, targeted therapy, and immunotherapy, have provided opportunities for conversion surgery in initially unresectable or borderline resectable cases, which significantly expand the pool of surgical candidates (7–10).
Due to its anatomical location, ICC resection frequently involves complex vascular and biliary reconstruction, thereby presenting considerable technical challenges and perioperative risks (11, 12). Surgical management has become more complicated due to the expanding use of neoadjuvant therapies. The dual aspects of antitumor efficacy and potential drug-induced liver injury contribute substantially to unclear surgical outcomes, underscoring the critical importance of precise surgical quality assessment in this context (13, 14). Several studies have indicated that surgical quality directly affects patient prognosis. For example, R0 resection has significantly improved survival rates (15, 16). However, current surgical outcome assessments often rely on isolated indicators (17), which lack integration and fail to provide a comprehensive reflection of overall treatment quality, despite their clinical relevance.
Textbook outcome (TO) is a multidimensional composite endpoint that incorporates multiple indicators such as R0 resection, no perioperative blood transfusion, no complications, no prolonged postoperative hospital stay, no unplanned readmission within 30 days, and no 30-day mortality (18, 19). TO was initially applied in colorectal cancer and is now increasingly adopted in ICC surgical evaluation and strongly correlated with improved long-term survival (18–21). Traditionally, chemotherapy-based neoadjuvant therapy was considered a negative predictor for TO, with studies indicating its potential to increase surgical risk (19, 22). However, with rapid advancements in targeted and immunotherapy, this perception warrants reevaluation. These novel therapies, characterized by higher response rates and improved safety profiles, may improve resectability, reduce surgical difficulty, and consequently facilitate TO achievement (23).
Therefore, using a cohort of patients with ICC and detailed neoadjuvant therapy information, this study aimed to investigate the association between TO and patient prognosis, identify clinical factors that are independently associated with TO achievement, and specifically assess the impact of neoadjuvant therapy—particularly regimens that incorporate targeted and immunotherapeutic agents—on TO. Furthermore, we developed and validated a TO-integrated prognostic prediction model to provide a practical tool to support clinical decision-making and surgical quality assessment.
Materials and methods
This retrospective cohort study consecutively enrolled patients who underwent resection for ICC at the Second Affiliated Hospital of Zhejiang University School of Medicine from May 2011 to September 2024. Inclusion criteria were pathological confirmation of ICC. Exclusion criteria were concomitant other malignancies, incomplete follow-up data, and missing information on tumor characteristics or surgical procedures.
Data were systematically collected on patient demographics [age, sex, and body mass index (BMI]), underlying disease (e.g., diabetes and hypertension), liver function parameters, and American Society of Anesthesiologists classification, tumor characteristics (e.g., size, T stage, differentiation, vascular invasion, lymph node metastasis, and distant metastasis), laboratory values [e.g., serum albumin (ALB), total bilirubin, prothrombin time (PT), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and alpha-fetoprotein (AFP)], and surgical details (e.g., scope of surgery, surgical method, lymph node dissection, operation time, and intraoperative blood loss). Further, information on neoadjuvant and adjuvant therapies was recorded, along with surgical quality indicators and postoperative survival outcomes.
TO was defined as the simultaneous achievement of the following six criteria: R0 resection, no perioperative transfusion, no postoperative complications, no 30-day mortality, no unplanned readmission within 30 days, and postoperative length of stay not exceeding the 75th percentile of the cohort (18, 19). Neoadjuvant therapy refers to preoperative systemic treatment, including chemotherapy, chemotherapy with targeted therapy, or immunotherapy, for patients with borderline resectable tumors. It may be considered for those with a large tumor burden, multifocal disease, or major vascular involvement. Additionally, for patients with technically resectable intrahepatic tumors but high-risk features for recurrence, neoadjuvant therapy may also be considered. The decision to administer neoadjuvant therapy or proceed directly with surgery also depends on the patient’s overall health, individual preferences, and other factors (24). Resections were classified as major (≥3 Couinaud’s segments) or minor (<3 segments) (25). Intraoperative blood loss and operation time were dichotomized according to median values.
The Shapiro–Wilk test was used to test continuous variables for normality. Normally distributed variables were expressed as mean ± standard deviation and compared using analysis of variance; non-normal variables were reported as median (interquartile range) and compared using non-parametric tests. Categorical variables were expressed as frequencies and percentages, compared with χ2 or Fisher’s exact test. Baseline characteristics and perioperative outcomes were compared between the TO and non-TO groups. Reasons for not achieving TO were analyzed. Univariate and multivariate logistic regression analyses, with additional in-depth evaluation focusing on neoadjuvant therapy, were conducted to identify factors associated with TO. Based on TO status, univariate and multivariate Cox regression analyses developed a prognostic model, visualized via a nomogram. Receiver operating characteristic (ROC) curves were used to assess discriminative ability. R (version 4.3.1) was used for analyses, with p-values of <0.05 indicating significance.
Results
Baseline characteristics and textbook outcomes
The study included 187 patients with a mean age of 61.88 ± 10.06 years, of whom 107 (57.2%) were male and 80 (42.8%) were female. Among these patients, 56 (29.9%) received neoadjuvant therapy. Of those, 13 patients (23.2%) received chemotherapy alone, while 43 patients (76.8%) received chemotherapy combined with targeted therapy or immunotherapy. A TO was achieved in 53 patients, constituting 28.3% of the entire cohort. Compared with patients who did not achieve TO, those who achieved TO had better nutritional reserves, as reflected by higher BMI (p = 0.008) and ALB (p = 0.001), as well as lower malignant potential indicated by CEA (p = 0.003) and reduced lymph node metastasis (p = 0.012). The scope of surgery exhibited no significant difference (p = 1.000); however, the TO group demonstrated a higher proportion of laparoscopic surgeries (p = 0.002), along with reduced intraoperative blood loss (p < 0.001) and shorter operation time (p = 0.003). Furthermore, the TO group received neoadjuvant therapy at a significantly higher rate (p = 0.007) (Table 1).
Table 1
| Characteristics | Total population N = 187 | Non-TO N = 134 | TO N = 53 | P-value |
|---|---|---|---|---|
| Age, years, mean (SD) | 61.88 (10.06) | 61.67 (9.75) | 62.40 (10.89) | 0.658 |
| Sex, n (%) | 0.700 | |||
| Female | 80 (42.8) | 59 (44.0) | 21 (39.6) | |
| Male | 107 (57.2) | 75 (56.0) | 32 (60.4) | |
| BMI, kg/m2, mean (SD) | 22.88 (3.07) | 22.51 (3.05) | 23.82 (2.95) | 0.008 |
| Underlying disease, n (%) | 0.535 | |||
| No | 128 (68.4) | 94 (70.1) | 34 (64.2) | |
| Yes | 59 (31.6) | 40 (29.9) | 19 (35.8) | |
| Child–Pugh score, n (%) | 0.191 | |||
| A | 170 (90.9) | 119 (88.8) | 51 (96.2) | |
| B | 17 (9.1) | 15 (11.2) | 2 (3.8) | |
| Total bilirubin, n (%) | 0.127 | |||
| <20 μmol/L | 151 (80.7) | 104 (77.6) | 47 (88.7) | |
| ≥20 μmol/L | 36 (19.3) | 30 (22.4) | 6 (11.3) | |
| Albumin, n (%) | 0.001 | |||
| ≤35 g/L | 34 (18.2) | 33 (24.6) | 1 (1.9) | |
| >35 g/L | 153 (81.8) | 101 (75.4) | 52 (98.1) | |
| Prothrombin time, n (%) | 0.379 | |||
| ≤13 s | 91 (48.7) | 62 (46.3) | 29 (54.7) | |
| >13 s | 96 (51.3) | 72 (53.7) | 24 (45.3) | |
| Carcinoembryonic antigen, n (%) | 0.003 | |||
| <5 ng/mL | 139 (74.3) | 91 (67.9) | 48 (90.6) | |
| ≥5 ng/mL | 48 (25.7) | 43 (32.1) | 5 (9.4) | |
| Carbohydrate antigen 19-9, n (%) | 0.283 | |||
| <37 U/mL | 75 (40.1) | 50 (37.3) | 25 (47.2) | |
| ≥37 U/mL | 112 (59.9) | 84 (62.7) | 28 (52.8) | |
| Alpha-fetoprotein, n (%) | 0.205 | |||
| <25 ng/mL | 180 (96.3) | 127 (94.8) | 53 (100.0) | |
| ≥25 ng/mL | 7 (3.7) | 7 (5.2) | 0 (0.0) | |
| Tumor diameter, n (%) | 0.894 | |||
| <5 cm | 102 (54.5) | 74 (55.2) | 28 (52.8) | |
| ≥5 cm | 85 (45.5) | 60 (44.8) | 25 (47.2) | |
| T stage, n (%) | 0.268 | |||
| T3–T4 | 32 (17.1) | 26 (19.4) | 6 (11.3) | |
| T1–T2 | 155 (82.9) | 108 (80.6) | 47 (88.7) | |
| Distant metastasis, n (%) | 1.000 | |||
| No | 186 (99.5) | 133 (99.3) | 53 (100.0) | |
| Yes | 1 (0.5) | 1 (0.7) | 0 (0.0) | |
| Lymph node metastasis, n (%) | 0.012 | |||
| No | 124 (66.3) | 81 (60.4) | 43 (81.1) | |
| Yes | 63 (33.7) | 53 (39.6) | 10 (18.9) | |
| AJCC stage, n (%) | 0.104 | |||
| I–II | 97 (51.9) | 64 (47.8) | 33 (62.3) | |
| III–IV | 90 (48.1) | 70 (52.2) | 20 (37.7) | |
| Degree of differentiation, n (%) | 0.644 | |||
| Low | 92 (49.2) | 64 (47.8) | 28 (52.8) | |
| Mild–high | 95 (50.8) | 70 (52.2) | 25 (47.2) | |
| Vascular invasion, n (%) | 0.489 | |||
| No | 118 (63.1) | 82 (61.2) | 36 (67.9) | |
| Yes | 69 (36.9) | 52 (38.8) | 17 (32.1) | |
| Surgical method, n (%) | 0.002 | |||
| Open | 160 (85.6) | 122 (91.0) | 38 (71.7) | |
| Laparoscopic | 27 (14.4) | 12 (9.0) | 15 (28.3) | |
| Lymph node dissection, n (%) | 0.094 | |||
| No | 19 (10.2) | 10 (7.5) | 9 (17.0) | |
| Yes | 168 (89.8) | 124 (92.5) | 44 (83.0) | |
| Scope of surgery, n (%) | 1.000 | |||
| Major | 166 (88.8) | 119 (88.8) | 47 (88.7) | |
| Minor | 21 (11.2) | 15 (11.2) | 6 (11.3) | |
| Intraoperative bleeding, n (%) | <0.001 | |||
| ≤200 mL | 95 (50.8) | 53 (39.6) | 42 (79.2) | |
| >200 mL | 92 (49.2) | 81 (60.4) | 11 (20.8) | |
| Operation time, n (%) | 0.003 | |||
| ≤285 min | 96 (51.3) | 59 (44.0) | 37 (69.8) | |
| >285 min | 91 (48.7) | 75 (56.0) | 16 (30.2) | |
| ASA classification, n (%) | 0.462 | |||
| ≤2 | 181 (96.8) | 131 (97.8) | 50 (94.3) | |
| >2 | 6 (3.2) | 3 (2.2) | 3 (5.7) | |
| Neoadjuvant therapy, n (%) | 0.007 | |||
| No | 131 (70.1) | 102 (76.1) | 29 (54.7) | |
| Yes | 56 (29.9) | 32 (23.9) | 24 (45.3) | |
| Adjuvant therapy, n (%) | 0.772 | |||
| No | 36 (19.3) | 27 (20.1) | 9 (17.0) | |
| Yes | 151 (80.7) | 107 (79.9) | 44 (83.0) |
Clinical characteristics of the total, textbook outcome (TO), and non-textbook outcome (non-TO) cohorts.
TO, textbook outcome; ASA, American Society of Anesthesiologists; AJCC, American Joint Committee on Cancer.
In the overall cohort, the primary reason for not achieving TO was complications (107 patients, 57.2%), followed by perioperative blood transfusion (59 patients, 31.6%), whereas 30-day mortality and positive resection margins exhibited a lesser impact (Figure 1A). Among patients who did not achieve TO, complications remained the predominant contributing factor (107 patients, 79.9%) (Figure 1B).
Figure 1
Factors influencing TO
Univariate logistic regression analysis identified BMI, ALB, CEA, lymph node metastasis, surgical method, intraoperative bleeding, operation time, and neoadjuvant therapy as factors affecting the achievement of TO (all p < 0.05; Table 2). Multivariate analysis further revealed BMI [odds ratio (OR) = 2.349, 95% confidence interval (CI): 1.108–5.077, p = 0.027], ALB (OR = 11.819, 95% CI: 2.173–222.448, p = 0.021), CEA (OR = 0.241, 95% CI: 0.073–0.667, p = 0.011), intraoperative bleeding (OR = 0.235, 95% CI: 0.101–0.514, p < 0.001), and neoadjuvant therapy (OR = 2.687, 95% CI: 1.234–5.969, p = 0.014) as independent predictors of TO (Table 2). A forest plot illustrates these independent factors (Figure 2A).
Table 2
| Characteristics | Univariate analysis | Multivariate analysis | P-value | |
|---|---|---|---|---|
| P-value | OR | 95% CI | ||
| Age, years | 0.237 | |||
| <65 | ||||
| ≥65 | ||||
| Sex | 0.583 | |||
| Female | ||||
| Male | ||||
| BMI | 0.004 | 0.027 | ||
| ≤23.9 kg/m2 | Reference | Reference | ||
| >23.9 kg/m2 | 2.349 | 1.108−5.077 | ||
| Underlying disease | 0.427 | |||
| No | ||||
| Yes | ||||
| Child–Pugh score | 0.130 | |||
| A | ||||
| B | ||||
| Total bilirubin | 0.090 | |||
| <20 μmol/L | ||||
| ≥20 μmol/L | ||||
| Albumin | 0.006 | 0.021 | ||
| ≤35 g/L | Reference | Reference | ||
| >35 g/L | 11.819 | 2.173–222.448 | ||
| Prothrombin time | 0.298 | |||
| ≤13 s | ||||
| >13 s | ||||
| Carcinoembryonic antigen | 0.003 | 0.011 | ||
| <5 ng/mL | Reference | Reference | ||
| ≥5 ng/mL | 0.241 | 0.073–0.667 | ||
| Carbohydrate antigen 19-9 | 0.216 | |||
| <37 U/mL | ||||
| ≥37 U/mL | ||||
| Alpha-fetoprotein | 0.986 | |||
| <25 ng/mL | ||||
| ≥25 ng/mL | ||||
| Tumor diameter | 0.767 | |||
| <5 cm | ||||
| ≥5 cm | ||||
| T stage | 0.191 | |||
| T3–T4 | ||||
| T1–T2 | ||||
| Distant metastasis | 0.988 | |||
| No | ||||
| Yes | ||||
| Lymph node metastasis | 0.008 | |||
| No | ||||
| Yes | ||||
| AJCC stage | 0.075 | |||
| I–II | ||||
| III–IV | ||||
| Degree of differentiation | 0.532 | |||
| Low | ||||
| Mild–high | ||||
| Vascular invasion | 0.391 | |||
| No | ||||
| Yes | ||||
| Surgical method | 0.001 | |||
| Open | ||||
| Laparoscopic | ||||
| Lymph node dissection | 0.058 | |||
| No | ||||
| Yes | ||||
| Scope of surgery | 0.980 | |||
| Major | ||||
| Minor | ||||
| Intraoperative bleeding | <0.001 | <0.001 | ||
| ≤200 mL | Reference | Reference | ||
| >200 mL | 0.235 | 0.101–0.514 | ||
| Operation time | 0.002 | |||
| ≤285 min | ||||
| >285 min | ||||
| ASA classification | 0.248 | |||
| ≤2 | ||||
| >2 | ||||
| Neoadjuvant therapy | 0.005 | 0.014 | ||
| No | Reference | Reference | ||
| Yes | 2.687 | 1.234–5.969 | ||
Logistic regression analysis of factors associated with textbook outcome.
CI, confidence interval; OR, odds ratio; ASA, American Society of Anesthesiologists; AJCC, American Joint Committee on Cancer.
Figure 2
Further analysis focused on the impact of neoadjuvant therapy on TO. Logistic regression was employed to examine its effects across six TO-related submetrics, with the results summarized in a forest plot (Figure 2B). Neoadjuvant therapy was significantly related to fewer postoperative complications (Figure 2B). Further composition analysis showed that, among patients who received neoadjuvant therapy, combination therapy was significantly associated with the achievement of TO (OR = 2.647, 95% CI: 1.277–5.482, p = 0.009), whereas chemotherapy alone was not significantly associated with TO achievement (p = 0.200).
Survival and prognostic modeling
Median survival was 30 months, with a median follow-up of 37 months. The Kaplan–Meier analysis revealed that TO was associated with better OS (p = 0.003) and recurrence-free survival (RFS) (p < 0.001) (Figure 3). Univariate analysis identified PT, CEA, AFP, lymph node metastasis, American Joint Committee on Cancer stage, TO, operation time, and adjuvant therapy as prognostic factors (all p < 0.05). Multivariate Cox regression confirmed PT [hazard ratio (HR) = 1.746, 95% CI: 1.118–2.728, p = 0.014], lymph node metastasis (HR = 3.055, 95% CI: 1.981–4.712, p < 0.001), TO (HR = 0.559, 95% CI: 0.315–0.991, p = 0.047), and adjuvant therapy (HR = 0.301, 95% CI: 0.192–0.473, p < 0.001) as independent predictors (Table 3).
Figure 3
Table 3
| Characteristics | Univariate analysis | Multivariate analysis | P-value | |
|---|---|---|---|---|
| P-value | HR | 95% CI | ||
| Age, years | 0.988 | |||
| <65 | ||||
| ≥65 | ||||
| Sex | 0.123 | |||
| Female | ||||
| Male | ||||
| BMI | 0.422 | |||
| ≤23.9 kg/m2 | ||||
| >23.9 kg/m2 | ||||
| Underlying disease | 0.645 | |||
| No | ||||
| Yes | ||||
| Child–Pugh score | 0.820 | |||
| A | ||||
| B | ||||
| Total bilirubin | 0.927 | |||
| <20 μmol/L | ||||
| ≥20 μmol/L | ||||
| Albumin | 0.680 | |||
| ≤35 g/L | ||||
| >35 g/L | ||||
| Prothrombin time | 0.001 | 0.014 | ||
| ≤13 s | Reference | Reference | ||
| >13 s | 1.746 | 1.118–2.728 | ||
| Carcinoembryonic antigen | <0.001 | |||
| <5 ng/mL | ||||
| ≥5 ng/mL | ||||
| Carbohydrate antigen 19-9 | 0.922 | |||
| <37 U/mL | ||||
| ≥37 U/mL | ||||
| Alpha-fetoprotein | 0.011 | |||
| <25 ng/mL | ||||
| ≥25 ng/mL | ||||
| Tumor diameter | 0.697 | |||
| <5 cm | ||||
| ≥5 cm | ||||
| T stage | 0.137 | |||
| T3–T4 | ||||
| T1–T2 | ||||
| Distant metastasis | 0.404 | |||
| No | ||||
| Yes | ||||
| Lymph node metastasis | <0.001 | <0.001 | ||
| No | Reference | Reference | ||
| Yes | 3.055 | 1.981–4.712 | ||
| AJCC stage | 0.005 | |||
| I–II | ||||
| III–IV | ||||
| Degree of differentiation | 0.294 | |||
| Low | ||||
| Mild–high | ||||
| Vascular invasion | 0.088 | |||
| No | ||||
| Yes | ||||
| Textbook outcome | 0.004 | 0.047 | ||
| No | Reference | Reference | ||
| Yes | 0.559 | 0.315–0.991 | ||
| Surgical method | 0.376 | |||
| Open | ||||
| Laparoscopic | ||||
| Lymph node dissection | 0.329 | |||
| No | ||||
| Yes | ||||
| Scope of surgery | 0.180 | |||
| Major | ||||
| Minor | ||||
| Intraoperative bleeding | 0.096 | |||
| ≤200 mL | ||||
| >200 mL | ||||
| Operation time | 0.024 | |||
| ≤285 min | ||||
| >285 min | ||||
| ASA classification | 0.644 | |||
| ≤2 | ||||
| >2 | ||||
| Neoadjuvant therapy | 0.143 | |||
| No | ||||
| Yes | ||||
| Adjuvant therapy | <0.001 | <0.001 | ||
| No | Reference | Reference | ||
| Yes | 0.301 | 0.192–0.473 | ||
Survival analysis based on textbook outcome status in patients with intrahepatic cholangiocarcinoma after surgery.
CI, confidence interval; HR, hazard ratio; ASA, American Society of Anesthesiologists; AJCC, American Joint Committee on Cancer.
Based on these independent predictors, a prognostic model that incorporates TO was developed and visualized as a nomogram for predicting survival for patients with ICC (Figure 4A). The model demonstrated good predictive ability, particularly for short-term prognosis, with area under the ROC curve values of 0.891 and 0.745 for 1- and 5-year survival, respectively (Figure 4B).
Figure 4
Discussion
Comprehensive surgical quality assessment is crucial for patient outcomes due to the technical complexity of ICC resection and challenging postoperative recovery. TO, a composite endpoint that integrates multiple perioperative indicators, has gained broad acceptance in evaluating the quality of liver surgery (18, 19). Specific definitions vary, but numerous studies have consistently associated TO with significantly improved survival (19–21). This study further confirms that achieving TO markedly improves both OS and RFS in patients with ICC. Using multivariate logistic regression, we identified CEA level, intraoperative blood loss, ALB, BMI, and neoadjuvant therapy as independent factors affecting TO attainment. A prognostic nomogram that incorporates TO and other independent factors demonstrated favorable discrimination and calibration in internal validation.
A key finding of this study is that neoadjuvant therapy—particularly regimens that combine chemotherapy with targeted or immunotherapy—is a positive predictor for TO. Pawlik et al. analyzed patients with ICC who underwent surgery between 1993 and 2015 and revealed that neoadjuvant chemotherapy was associated with a lower TO rate (p = 0.04) (19). Separately, another study that incorporated data from 2000 to 2022 indicated that neoadjuvant therapy served as a negative factor for TO (22). This discrepancy may stem from evolving treatment paradigms. The majority of patients (77.19%) in our cohort received combination neoadjuvant therapy. Compared with chemotherapy alone, targeted and immunotherapies provide greater precision and an improved safety profile, which potentially facilitates tumor downstaging, reduces micrometastatic burden, and preserves liver function and overall condition, thereby enabling safer and more complete resection (26, 27). High-level clinical evidence, such as the KEYNOTE-966 and TOPAZ-1 phase III trials, which demonstrated survival benefits of immunotherapy–chemotherapy combinations in advanced biliary tract cancer, further support this perspective (28, 29). A phase II study by Guoming Shi et al. reported promising efficacy and safety for tislelizumab in combination with lenvatinib and GEMOX (gemcitabine and oxaliplatin) in the neoadjuvant setting (9). Further, neoadjuvant immunotherapy has been associated with higher TO rates in other malignancies, including esophageal cancer (23), which corroborates our findings. Notably, novel formulations (e.g., nab-paclitaxel and liposomal irinotecan) may improve both efficacy and safety by optimizing drug delivery (30, 31), potentially leading to better perioperative outcomes, even within the same class of chemotherapeutic agents.
Although neoadjuvant therapy significantly improved textbook outcomes for surgical patients in this study, some patients still experienced rapid disease progression shortly after treatment. In these cases, the tumors were often highly resistant to treatment and exhibited aggressive biological behavior. Preoperative disease progression can avoid unnecessary and ineffective surgery, thereby reducing the risk of early postoperative recurrence (32). This further emphasizes the clinical value of neoadjuvant therapy, as it aids in identifying patients who are unlikely to benefit from surgery and supports more informed decision-making.
Other factors associated with TO hold clinical relevance. CEA elevation is a biomarker of aggressive tumor biology and generally indicates an increased tumor burden, which may consequently elevate the complexity of surgical intervention (33, 34). ALB and BMI reflect nutritional and baseline status. Increased ALB levels have been associated with a higher rate of TO (35). Some studies have indicated that a BMI of ≥30 kg/m2 may negatively affect TO (36); however, in the present cohort, the mean BMI was 22.88 kg/m2, and no patient reached a BMI of 30 kg/m2. These findings indicate that population characteristics, regional variations, and other factors may influence the association between BMI and TO (37, 38), which warrants further investigation for clarity. Intraoperative blood loss is a critical determinant of TO, closely associated with perioperative transfusion, which is itself associated with increased infection risk and worse survival (39).
The prognostic model developed herein integrated TO, PT, lymph node metastasis, and adjuvant therapy, which demonstrates good predictive performance. The role of adjuvant therapy (e.g., capecitabine and S1) is well-established from phase III trials such as BILCAP and JCOG1202 (40, 41). Lymph node metastasis is a recognized poor prognostic factor, and adequate dissection (≥6 nodes) is crucial for accurate staging (42). Prolonged PT may indicate impaired liver function, tumor burden, and systemic inflammation (43).
Compared with previous studies, our work highlights the evolving landscape of neoadjuvant therapy, particularly the positive impact of combination targeted/immunotherapy on TO. The inclusion of variables spanning preoperative patient status, tumor features, surgical details, and perioperative treatments improves the model’s comprehensiveness and utility. Limitations include its single-center, retrospective design, limited sample size, and potential selection bias. Thus, validation through multicenter, larger cohorts is warranted. Heterogeneity in neoadjuvant regimens (e.g., drug combinations, cycles, and molecular subtypes) may affect outcomes (44, 45), requiring subgroup analyses with expanded samples. Furthermore, the lack of a globally standardized TO definition and the potential influence of institutional policies and recovery pathways on metrics, such as postoperative length of stay (46, 47), underscore the need for consensus-building.
Conclusion
This study confirms that achieving TO significantly improves survival in patients with ICC and identifies CEA, intraoperative blood loss, ALB, BMI, and neoadjuvant therapy as independent influencing factors. Notably, this study is the first to report that neoadjuvant regimens that combine chemotherapy with targeted or immunotherapy improve TO attainment, which provides crucial evidence for neoadjuvant therapy strategies in ICC. The developed nomogram demonstrates robust prognostic predictive ability, thereby offering a practical tool for individualized clinical decision-making and surgical quality assessment.
Statements
Data availability statement
The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy and confidentiality concerns, as well as the conditions stipulated by the ethical approval and data use agreement. However, de-identified data can be made available from the corresponding author upon reasonable request, subject to approval of a research proposal and a data sharing agreement. Requests to access the datasets should be directed to JH, hujiawei0714@163.com.
Ethics statement
The studies involving humans were approved by Human Research Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine. The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because This study plans to include patients spanning many years (2011–2024). Many patients are very old, their contact information has changed or expired, and objectively cannot be contacted. High loss to follow-up rate and death: The subjects of this study are patients who have undergone surgery for intrahepatic bile duct cancer. The prognosis of this disease is poor, and a considerable proportion of patients have died, and their informed consent cannot be obtained. For surviving patients, there is also an extremely high loss to follow-up rate due to long time after surgery, interrupted follow-up, etc. Huge feasibility challenge: If all eligible patients or their close relatives are to be contacted, huge manpower, time and financial costs will be required, which is far beyond the affordability of this research team, and the proportion of successful consent will be extremely low, thereby introducing an unevaluable selection bias, which seriously damages the scientific value and authenticity of the research results.
Author contributions
JH: Conceptualization, Data curation, Formal Analysis, Writing – original draft, Writing – review & editing. YW: Formal Analysis, Methodology, Writing – original draft, Writing – review & editing. HD: Data curation, Validation, Writing – original draft. SM: Visualization, Writing – original draft. XZ: Visualization, Writing – original draft. QL: Methodology, Writing – review & editing. YP: Project administration, Supervision, Validation, Writing – original draft. YJ: Formal Analysis, Validation, Writing – review & editing. YY: Validation, Writing – review & editing. JL: Conceptualization, Funding acquisition, Investigation, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. Supported by the Key research and development program of Zhejiang Province, No. 2024C03172.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was used in the creation of this manuscript. Generative AI (specifically, DeepSeek Chat) was used to polish and refine the language in this manuscript. It assisted with improving sentence fluency, grammar, and overall clarity of expression. The core ideas, research data, analysis, and conclusions remain entirely our own. All authors have reviewed and edited the AI-generated suggestions and take full responsibility for the entire content of the publication.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
NakeebAPittHASohnTAColemanJAbramsRAPiantadosiSet al. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. (1996) 224:463–73; discussion 73-5. doi: 10.1097/00000658-199610000-00005
2
MosconiSBerettaGDLabiancaRZampinoMGGattaGHeinemannV. Cholangiocarcinoma. Crit Rev Oncol Hematol. (2009) 69:259–70. doi: 10.1016/j.critrevonc.2008.09.008
3
SungHFerlayJSiegelRLLaversanneMSoerjomataramIJemalAet al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. (2021) 71:209–49. doi: 10.3322/caac.21660
4
KohKCLeeHChoiMSLeeJHPaikSWYooBCet al. Clinicopathologic features and prognosis of combined hepatocellular cholangiocarcinoma. Am J Surg. (2005) 189:120–5. doi: 10.1016/j.amjsurg.2004.03.018
5
WeberSMRiberoDO’ReillyEMKokudoNMiyazakiMPawlikTM. Intrahepatic cholangiocarcinoma: expert consensus statement. HPB (Oxford). (2015) 17:669–80. doi: 10.1111/hpb.12441
6
LiguoriCCacciaguerraABGiampieriRMocchegianiFSciortinoCVivarelliMet al. Is it a new era for intrahepatic cholangiocarcinoma? Crit Rev Oncol Hematol. (2025) 215:104923. doi: 10.1016/j.critrevonc.2025.104923
7
European Association for the Study of the Liver. EASL-ILCA Clinical Practice Guidelines on the management of intrahepatic cholangiocarcinoma. J Hepatol. (2023) 79:181–208. doi: 10.1016/j.jhep.2023.03.010
8
BensonABD’AngelicaMIAbramsTAbbottDEAhmedAAnayaDAet al. NCCN guidelines® Insights: biliary tract cancers, version 2.2023. J Natl Compr Canc Netw. (2023) 21:694–704. doi: 10.6004/jnccn.2023.0035
9
ShiGHuangXLiXLiangFGaoQZhangDet al. Conversion therapy of tislelizumab plus lenvatinib and GEMOX in unresectable locally advanced biliary tract cancer (ZSAB-TransGOLP): a multicentre, prospective, phase 2 study. Lancet Oncol. (2025) 26:1344–5. doi: 10.1016/s1470-2045(25)00376-6
10
MaithelSKKeilsonJMCaoHSTRupjiMMahipalALinBSet al. NEO-GAP: A single-arm, phase II feasibility trial of neoadjuvant gemcitabine, cisplatin, and nab-paclitaxel for resectable, high-risk intrahepatic cholangiocarcinoma. Ann Surg Oncol. (2023) 30:6558–66. doi: 10.1245/s10434-023-13809-5
11
BealEWCloydJMPawlikTM. Surgical treatment of intrahepatic cholangiocarcinoma: current and emerging principles. J Clin Med. (2020) 10:104. doi: 10.3390/jcm10010104
12
LangHSotiropoulosGCSgourakisGSchmitzKJPaulAHilgardPet al. Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients. J Am Coll Surg. (2009) 208:218–28. doi: 10.1016/j.jamcollsurg.2008.10.017
13
MalkaDCerveraPFoulonSTrarbachTde la FouchardièreCBoucherEet al. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol. (2014) 15:819–28. doi: 10.1016/s1470-2045(14)70212-8
14
TseRVHawkinsMLockwoodGKimJJCummingsBKnoxJet al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. (2008) 26:657–64. doi: 10.1200/jco.2007.14.3529
15
DeOliveiraMLCunninghamSCCameronJLKamangarFWinterJMLillemoeKDet al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg. (2007) 245:755–62. doi: 10.1097/01.sla.0000251366.62632.d3
16
PatelT. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. (2001) 33:1353–7. doi: 10.1053/jhep.2001.25087
17
ChenXWeiXYueLXiaoY. Efficacy and safety of preoperative biliary drainage in patients with Hilar Cholangiocarcinoma: a systematic review and meta-analysis. Int J Surg. (2025) 111:3543–60. doi: 10.1097/js9.0000000000002324
18
KolfschotenNEKievitJGooikerGAvan LeersumNJSnijdersHSEddesEHet al. Focusing on desired outcomes of care after colon cancer resections; hospital variations in ‘textbook outcome’. Eur J Surg Oncol. (2013) 39:156–63. doi: 10.1016/j.ejso.2012.10.007
19
MerathKChenQBaganteFAlexandrescuSMarquesHPAldrighettiLet al. A multi-institutional international analysis of textbook outcomes among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma. JAMA Surg. (2019) 154:e190571. doi: 10.1001/jamasurg.2019.0571
20
GuptaVMorAMundhadaROKaziMKDaphalAJSharmaAet al. Textbook outcomes of minimally invasive total mesorectal excision: A composite tool to assess and compare outcomes for benchmarking. Dis Colon Rectum. (2025) 68:1042–51. doi: 10.1097/dcr.0000000000003837
21
CarusoGAinioCFumagalliDReynoldsEANasioudisDMc GreeMEet al. Textbook oncologic outcome in endometrial cancer surgery: A quality measure to improve survival and address disparities. Gynecol Oncol. (2025) 200:33–43. doi: 10.1016/j.ygyno.2025.07.009
22
AltafAKhalilMAkabaneMRashidZKawashimaJZindaniSet al. Textbook outcome in liver surgery for intrahepatic cholangiocarcinoma: defining predictors of an optimal postoperative course using machine learning. HPB (Oxford). (2025) 27:402–13. doi: 10.1016/j.hpb.2024.12.013
23
KalffMCVesseurIEshuisWJHeinemanDJDaamsFvan der PeetDLet al. The association of textbook outcome and long-term survival after esophagectomy for esophageal cancer. Ann Thorac Surg. (2021) 112:1134–41. doi: 10.1016/j.athoracsur.2020.09.035
24
Chinese Society of Liver Cancer Cholangiocarcinoma Cooperative GFanJ. Chinese expert consensus on management of intrahepatic cholangiocarcinoma (2022 edition). Chin J Digest Surg. (2022) 21:1269–301. doi: 10.3760/cma.j.cn115610-20220829-00476
25
PangYY. The Brisbane 2000 terminology of liver anatomy and resections. HPB 2000; 2:333-39. HPB (Oxford). (2002) 4:99; author reply –100. doi: 10.1080/136518202760378489
26
LiuJJZhouMYuanTHuangZYZhangZY. Conversion treatment for advanced intrahepatic cholangiocarcinoma: Opportunities and challenges. World J Gastroenterol. (2025) 31:104901. doi: 10.3748/wjg.v31.i15.104901
27
WuGChenXLuoRKohYXLimTKHChewVet al. Histopathologic grading of residual tumor predicts survival of intrahepatic cholangiocarcinoma patients treated with neoadjuvant therapy: major pathologic response and its clinical significance. Am J Surg Pathol. (2025) 49:578–87. doi: 10.1097/pas.0000000000002359
28
KelleyRKUenoMYooCFinnRSFuruseJRenZet al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. (2023) 401:1853–65. doi: 10.1016/s0140-6736(23)00727-4
29
OhDYHeARBouattourMOkusakaTQinSChenLTet al. Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study. Lancet Gastroenterol Hepatol. (2024) 9:694–704. doi: 10.1016/s2468-1253(24)00095-5
30
EttrichTJModestDPSinnMStrieflerJKOpitzBGoetzeTet al. Nanoliposomal irinotecan with fluorouracil and leucovorin or gemcitabine plus cisplatin in advanced cholangiocarcinoma: A phase II study of the AIO hepatobiliary-YMO cancer groups (NIFE-AIO-YMO HEP-0315). J Clin Oncol. (2024) 42:3094–104. doi: 10.1200/jco.23.01566
31
SurinachAPhungTAbdul-RahimOKhushmanM. Prolonged response to liposomal irinotecan in a patient with stage IV pancreatic/bile duct cancer previously treated with FOLFIRINOX and gemcitabine plus nab-paclitaxel. Curr Oncol. (2020) 27:e222–e5. doi: 10.3747/co.27.5893
32
TsilimigrasDISaharaKWuLMorisDBaganteFGuglielmiAet al. Very early recurrence after liver resection for intrahepatic cholangiocarcinoma: considering alternative treatment approaches. JAMA Surg. (2020) 155:823–31. doi: 10.1001/jamasurg.2020.1973
33
ZhangNYangYLinKQiaoBYangDPJinDDet al. Contrast-enhanced ultrasound for diagnosing subtypes of intrahepatic cholangiocarcinoma: a comparative study with poorly differentiated hepatocellular carcinoma. Cancer Imaging. (2025) 25:107. doi: 10.1186/s40644-025-00923-8
34
WangQQianXZhangYQianBMaXYangCet al. Multi-regional radiomics for predicting microvascular invasion and lymph node metastasis in intrahepatic cholangiocarcinoma. Clin Radiol. (2025) 88:106979. doi: 10.1016/j.crad.2025.106979
35
YuYChangyongELinCWangLJiangT. Safety and learning curve analysis of robotic-assisted pancreaticoduodenectomy: experience of a single surgeon. J Robot Surg. (2024) 18:92. doi: 10.1007/s11701-024-01844-7
36
GenserLLimCBarbierLRegimbeauJMHobeikaCGoumardCet al. Assessment of factors associated with morbidity and textbook outcomes of laparoscopic liver resection in obese patients: A french nationwide study. J Am Coll Surg. (2022) 235:159–71. doi: 10.1097/xcs.0000000000000221
37
VelayudhamGKDermanisAKamarajahSKGriffithsEA. Predictors of textbook outcome following oesophagogastric cancer surgery. Dis Esophagus. (2024) 37:doae023. doi: 10.1093/dote/doae023
38
TakaokaSHamadaTTakaharaNFukudaRHakutaRIshigakiKet al. Body mass index and survival among patients with advanced biliary tract cancer: a single-institutional study with nationwide data-based validation. J Gastroenterol. (2024) 59:732–43. doi: 10.1007/s00535-024-02124-9
39
DogeasEGellerDATohmeSSteelJLoWMoroccoBet al. Textbook outcomes after open live donor right hepatectomy and open right hepatic lobectomy for cancer in 686 patients: redefining the benchmark. Ann Surg. (2023) 278:e256–e63. doi: 10.1097/sla.0000000000005749
40
BridgewaterJFletcherPPalmerDHMalikHZPrasadRMirzaDet al. Long-term outcomes and exploratory analyses of the randomized phase III BILCAP study. J Clin Oncol. (2022) 40:2048–57. doi: 10.1200/jco.21.02568
41
NakachiKIkedaMKonishiMNomuraSKatayamaHKataokaTet al. Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. (2023) 401:195–203. doi: 10.1016/s0140-6736(22)02038-4
42
ZhangXFXueFDongDHWeissMPopescuIMarquesHPet al. Number and station of lymph node metastasis after curative-intent resection of intrahepatic cholangiocarcinoma impact prognosis. Ann Surg. (2021) 274:e1187–e95. doi: 10.1097/sla.0000000000003788
43
LiXSunZLiXWangQChenMZhangBet al. Biomarkers for predicting the prognosis of intrahepatic cholangiocarcinoma: A retrospective single-center study. Med (Baltimore). (2023) 102:e33314. doi: 10.1097/md.0000000000033314
44
SongYBoernerTDrillEShinPKumarSSigelCet al. A novel approach to quantify heterogeneity of intrahepatic cholangiocarcinoma: the hidden-genome classifier. Clin Cancer Res. (2024) 30:3499–511. doi: 10.1158/1078-0432.Ccr-24-0657
45
HuangSHuaCDingBChenJZhengSDingC. Advances in improving the efficacy of anti-PD-1/PD-L1 therapy in intrahepatic cholangiocarcinoma. Crit Rev Oncol Hematol. (2025) 213:104784. doi: 10.1016/j.critrevonc.2025.104784
46
AlaimoLEndoYCatalanoGRuzzenenteAAldrighettiLWeissMet al. Benchmarks in liver resection for intrahepatic cholangiocarcinoma. Ann Surg Oncol. (2024) 31:3043–52. doi: 10.1245/s10434-023-14880-8
47
GosseJMarianiPCotteEPassotGGermainADetryOet al. Optimal results through enhanced recovery: Achieving textbook outcomes with high compliance in elective liver surgery. World J Surg. (2024) 48:2736–48. doi: 10.1002/wjs.12345
Summary
Keywords
immunotherapy, intrahepatic cholangiocarcinoma, neoadjuvant therapy, prognostic model, targeted therapy, textbook outcomes
Citation
Hu J, Wang Y, Diao H, Miao S, Zhang X, Li Q, Pan Y, Jin Y, Yu Y and Li J (2026) Determinants and survival benefits of achieving textbook outcome for intrahepatic cholangiocarcinoma in the era of neoadjuvant therapy. Front. Oncol. 16:1737204. doi: 10.3389/fonc.2026.1737204
Received
01 November 2025
Revised
26 December 2025
Accepted
05 January 2026
Published
22 January 2026
Volume
16 - 2026
Edited by
Zhao Li, Peking University People’s Hospital, China
Reviewed by
Chen Yuan, Jiangxi Cancer Hospital, China
Guangbing Li, Shandong Provincial Hospital, China
Updates
Copyright
© 2026 Hu, Wang, Diao, Miao, Zhang, Li, Pan, Jin, Yu and Li.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jiangtao Li, zrljt@zju.edu.cn
These authors share first authorship
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.