Accurate risk stratification and patient selection is necessary to identify patients who will benefit the most from surgery or be better treated with other non-surgical treatment strategies. We sought to identify which patients in the preoperative setting would likely derive the most or least benefit from resection of intrahepatic cholangiocarcinoma (ICC). Patients who underwent curative-intent resection for ICC between 1990 and 2017 were identified from an international multi-institutional database. A machine-based classification and regression tree (CART) was used to generate homogeneous groups of patients relative to overall survival (OS) based on preoperative factors. Among 1146 patients, CART analysis revealed tumor number and size, albumin-bilirubin (ALBI) grade and preoperative lymph node (LN) status as the strongest prognostic factors associated with OS among patients undergoing resection for ICC. In turn, four groups of patients with distinct outcomes were generated through machine learning: Group 1 (n = 228): single ICC, size ≤ 5 cm, ALBI grade I, negative preoperative LN status; Group 2 (n = 708): (1) single tumor > 5 cm, (2) single tumor ≤ 5 cm, ALBI grade 2/3, and (3) single tumor ≤ 5 cm, ALBI grade 1, metastatic/suspicious LNs; Group 3 (n = 150): 2–3 tumors; Group 4 (n = 60): ≥ 4 tumors. 5-year OS among Group 1, 2, 3, and 4 patients was 60.5%, 35.8%, 27.5%, and 3.8%, respectively (p < 0.001). Similarly, 5-year disease-free survival (DFS) among Group 1, 2, 3, and 4 patients was 47%, 27.2%, 6.8%, and 0%, respectively (p < 0.001). The machine-based CART model identified distinct prognostic groups of patients with distinct outcomes based on preoperative factors. Survival decision trees may be useful as guides in preoperative patient selection and risk stratification.

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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.

Cholangiocarcinoma accounts for approximately 10% of all hepatobiliary tumors and represents 3% of all new-diagnosed malignancies worldwide. Intrahepatic cholangiocarcinoma (i-CCA) accounts for 10% of all cases, perihilar (h-CCA) cholangiocarcinoma represents two-thirds of the cases, while distal cholangiocarcinoma accounts for the remaining quarter. Originally described by Klatskin in 1965, h-CCA represents one of the most challenging tumors for hepatobiliary surgeons, mainly because of the anatomical vascular relationships of the biliary confluence at the hepatic hilum. Surgery is the only curative option, with the goal of a radical, margin-negative (R0) tumor resection. Continuous efforts have been made by hepatobiliary surgeons in order to achieve R0 resections, leading to the progressive development of aggressive approaches that include extended hepatectomies, associating liver partition, and portal vein ligation for staged hepatectomy, pre-operative portal vein embolization, and vascular resections. i-CCA is an aggressive biliary cancer that arises from the biliary epithelium proximal to the second-degree bile ducts. The incidence of i-CCA is dramatically increasing worldwide, and surgical resection is the only potentially curative therapy. An aggressive surgical approach, including extended liver resection and vascular reconstruction, and a greater application of systemic therapy and locoregional treatments could lead to an increase in the resection rate and the overall survival in selected i-CCA patients. Improvements achieved over the last two decades and the encouraging results recently reported have led to liver transplantation now being considered an appropriate indication for CCA patients.

https://www.mdpi.com/2072-6694/13/15/3657/pdf

Current Surgical Management of Peri-Hilar and Intra-Hepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy and is increasing in incidence. Long-term outcomes are optimized when patients undergo margin-negative resection followed by adjuvant chemotherapy. Unfortunately, a significant proportion of patients present with locally advanced, unresectable disease. Furthermore, recurrence rates are high even among patients who undergo surgical resection. The delivery of systemic and/or liver-directed therapies prior to surgery may increase the proportion of patients who are eligible for surgery and reduce recurrence rates by prioritizing early systemic therapy for this aggressive cancer. Nevertheless, the available evidence for neoadjuvant therapy in ICC is currently limited yet recent advances in liver directed therapies, chemotherapy regimens, and targeted therapies have generated increasing interest its role. In this article, we review the rationale for, current evidence for, and ongoing research efforts in the use of neoadjuvant therapy for ICC.

Neoadjuvant treatment strategies for intrahepatic cholangiocarcinoma

Biliary tract cancers (BTCs) comprise a heterogenous group of aggressive and rare malignancies arising in the bile duct outside or within the liver. BTCs include cholangiocarcinoma (CCA), gallbladder cancer (GBC) and ampulla of Vater cancer (AVC); according to the "historical" anatomical classification, CCAs are further subdivided into extrahepatic cholangiocarcinomas (eCCAs) - including distal (dCCA) and perihilar (pCCA) - and intrahepatic cholangiocarcinomas (iCCA). Notably enough, these subtypes reflect distinct features in terms of biology, epidemiology, prognosis and therapeutic strategies. Although surgical resection remains the only potentially curative treatment option for CCA patients, radical surgery is possible for only a small proportion of cases. Moreover, it has been observed that up to 50% of patients deemed resectable at diagnosis are found to be unresectable during exploratory laparotomy. Additionally, even following radical surgery, recurrence rates are high. Neoadjuvant therapy represents an appealing approach in this setting, where this therapeutic strategy has the potential to improve local and distant control, to achieve R0 resection and to prevent distant metastasis. However, few data are currently available supporting neoadjuvant therapy in CCA and several questions remains unanswered, including the activity of systemic therapy in early stages of the disease, the optimal start time of treatment, patient selection and the length of neoadjuvant therapy. In this review, we will discuss available data on neoadjuvant systemic therapy in CCA, highlighting future directions in this setting, with a particular focus on recently published data and ongoing and recruiting trials.

Neoadjuvant therapy for cholangiocarcinoma: A comprehensive literature review

Upfront surgery is the current standard for resectable intrahepatic cholangiocarcinoma (ICC) despite high treatment failure with this approach. We sought to examine the use of neoadjuvant chemotherapy (NAC) as an alternative strategy for this population. The National Cancer Database was used to identify patients with resectable ICC undergoing curative-intent surgery (2006–2014). Utilization trends were examined and survival estimates between NAC and upfront surgery were compared; propensity score-matched models were used to examine the association of NAC with overall survival (OS) for all patients and risk-stratified cohorts. Models accounted for clustering within hospitals, and results represent findings from a complete-case analysis. Among 881 patients with ICC, 8.3% received NAC, with no changes over time (Cochran–Armitage p = 0.7). Median follow-up was 50.9 months, with no difference in unadjusted survival with NAC versus upfront surgery (median OS 51.8 vs. 35.6 months, and 5-year OS rates of 38.2% vs. 36.6%; log rank p = 0.51), and no survival benefit in the propensity score-matched analysis (hazard ratio [HR] 0.78, 95% CI 0.54–1.11; p = 0.16). However, for patients with stage II–III disease, NAC was associated with a trend towards improved survival (median OS of 47.6 months vs. 25.9 months, and 5-year OS rates of 34% vs. 25.7%; log-rank p = 0.10) and a statistically significant survival benefit in the propensity score-matched analysis. (HR 0.58, 95% CI 0.37–0.91; p = 0.02). NAC is associated with improved OS over upfront surgery in patients with resectable ICC and high-risk of treatment failure. These data support the need for prospective studies to examine NAC as an alternative strategy to improve OS in this population.

Neoadjuvant Chemotherapy for Intrahepatic Cholangiocarcinoma: A Propensity Score Survival Analysis Supporting Use in Patients with High-Risk Disease

Background Chemotherapy is frequently used in cholangiocarcinoma as an adjunct to surgical resection, but the appropriate sequence of chemotherapy with surgery is unclear. Patients and methods Using the National Cancer Database, we identified patients who underwent surgery and chemotherapy for stage I-III cholangiocarcinoma between 2006 and 2014. The propensity score reflecting the probability of receiving neoadjuvant chemotherapy was estimated by multivariate logistic regression method. Patients in the neoadjuvant and adjuvant chemotherapy study arms were then propensity-matched in 1:3 ratios using the nearest neighbor method. Overall Survival (OS) in the matched data set was estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using Cox proportional hazard regression model. Results Of the 1450 patients who met our inclusion criteria, 299 (20.6%) received neoadjuvant chemotherapy while 1151 (79.3%) received adjuvant chemotherapy. The median age at diagnosis was 63 years. 278 patients in the neoadjuvant group were matched to 700 patients in the adjuvant group. In the matched cohort, patients who received neoadjuvant chemotherapy had a superior OS compared to those who received adjuvant chemotherapy (Median OS: 40.3 vs. 32.8 months; HR: 0.78; 95% CI: 0.64–0.94, p = 0.01). The 1- and 5-year OS rates for the neoadjuvant chemotherapy group were 85.8% and 42.5% respectively compared to 84.6% and 31.7% for the adjuvant chemotherapy group. Conclusion In this large national database study, neoadjuvant chemotherapy was associated with a longer OS in a select group of patients with cholangiocarcinoma compared to those who underwent upfront surgical resection followed by adjuvant chemotherapy.

Irbaz Bin-Riaz

Papers

Neoadjuvant vs. adjuvant chemotherapy for cholangiocarcinoma: A propensity score matched analysis.