Multifocal Intrahepatic Cholangiocarcinoma Research Articles

Prognostic implications of tumor histology and microenvironment in surgically resected intrahepatic cholangiocarcinoma: a single institutional experience.

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignant neoplasm. Certain histologic features and the tumor microenvironment may impact disease progression. We aim to characterize the clinicopathologic features of ICC to identify prognostic factors. A total of 50 surgically resected ICC (partial or transplant) cases were analyzed. The cohort included 26 men and 24 women with a median age of 62years. Eighteen (36%) cases were multifocal ICC with a mean largest tumor size of 6.5cm. Neoadjuvant and adjuvant chemotherapy was done in eight (16%) and 33 (66%) patients, respectively. Histologically, 42 (84%) were small duct type, seven (14%) large duct type, and one mixed (2%). Thirty (60%) cases showed lymphovascular invasion (LVI) and 11 (22%) with perineural invasion (PNI). Twenty-eight (56%) cases demonstrated dense intratumoral hyaline fibrosis and 18 (36%) with tumor necrosis, each ≥ 10% tumor volume. On follow-up, 35 (70%) patients died of disease after a median disease-specific survival (DSS) of 21months. Univariate analysis revealed that hyaline fibrosis and adjuvant chemotherapy were associated with better DSS, while tumor size, multifocality, necrosis, and peritumoral neutrophil to lymphocyte ratio were associated with worse DSS. In contrast, age, sex, small vs. large duct types, LVI, and individual inflammatory cell counts were not significant prognostic factors. In summary, ICC is a heterogeneous malignancy with variable clinical courses associated with tumor burden, histology, and microenvironment. Targeting specific components within the tumor microenvironments may be a promising approach for treatment in the future.

A phase II trial of induction systemic mFOLFIRINOX followed by hepatic arterial infusion of floxuridine and dexamethasone given concurrently with systemic mFOLFIRI as a first-line therapy in patients with unresectable liver-dominant intrahepatic cholangiocarcinoma (HELIX-1).

511 Background: Most patients with intrahepatic cholangiocarcinoma (ICC) have unresectable or multifocal liver-dominant disease. Survival after first-line systemic therapy remains poor, with median progression-free (mPFS) and overall survival of 7.2 and 12.8 months, respectively. Hepatic arterial infusion (HAI) therapy with floxuridine maximizes liver-specific treatment with minimal systemic toxicity and potentially offers improved disease control when combined with systemic therapy. Methods: HELIX-1 (NCT04251715) is an investigator-initiated, first-line, single-center, single-arm phase II clinical trial for patients with liver-dominant unresectable or multifocal ICC. The trial was designed with a patient safety run-in evaluating toxicity from the combined therapy. Pre-trial screening included laparoscopy, biopsies, and PET/CT. Eligible patients were treated with systemic mFOLFIRINOX for 4 cycles in order to select those likely to benefit from HAI. Patients with disease control on restaging proceeded to HAI pump placement and treatment with HAI floxuridine for 14 days followed by systemic mFOLFIRI on a 28-day cycle. The co-primary objectives were to assess safety of the combined therapeutic strategy and the disease control rate (DCR) at 6 months (RECIST v1.1) at end of trial (EOT). Results: A total of n=5 patients with liver-only ICC enrolled in the trial and completed the entire study protocol. The median age was 60 years (range 42-69) with a dominant lesion size of 9.8cm (range 8.4-14.5). All patients had both right and left hemiliver involvement with a median of 9 intrahepatic tumors (range 1-15). No patients experienced grade 3 or 4 adverse events, or hepatic dysfunction leading to cessation of HAI therapy. The DCR at 6 months was 100%, with a mPFS of 18.2 months. All five patients achieved partial radiographic response (PR) while receiving HAI therapy, and remain alive with liver-only disease at a median of 18.4 months (range 12.7-20) after study enrollment. After continuing treatment with HAI and systemic mFOLFIRI beyond the EOT, two patients transitioned to HAI treatment only and then to biochemical and radiographic surveillance without therapy after demonstrating PR and CA19-9 normalization. Conclusions: Integration of HAI floxuridine with mFOLFIRI following mFOLFIRINOX induction for patients with liver-only advanced ICC is well-tolerated and demonstrates longer DCR in comparison to historical controls. The combined regimen minimized systemic toxicity and allowed a large proportion of patients to transition to liver-only HAI treatment with maintained disease control. Future directions include combining HAI with new first-line systemic regimens for patients with advanced ICC. Clinical trial information: NCT04251715 .

Radioembolization with Yttrium-90 Glass Microspheres as a First-Line Treatment for Unresectable Intrahepatic Cholangiocarcinoma—A Prospective Feasibility Study

PurposeTo evaluate the safety and effectiveness of yttrium-90 (90Y) radioembolization as first-line treatment for unresectable intrahepatic cholangiocarcinoma (ICC). Materials and MethodsThis prospective study enrolled patients who had never received chemotherapy, liver embolization, and radiation therapy. The tumors were solitary in 16 patients, multiple in 8 patients, unilobar in 14 patients, and bilobar in 10 patients. Patients underwent transarterial radioembolization with 90Y-labeled glass microspheres. The primary end point was hepatic progression-free survival (HPFS). Secondary end points were overall survival (OS), tumor response, and toxicity. ResultsTwenty-four patients (age, 72.3 years ± 9.3; 12 women) were included in the study. The median delivered radiation dose was 135.5 Gy (interquartile range, 77.6 Gy). The median HPFS was 5.5 months (95% CI, 3.9–7.0 months). Analysis failed to identify any prognostic factor associated with HPFS. Imaging response at 3 months showed 56% disease control, and the best radiographic response was 71% disease control. The median OS from the radioembolization treatment was 19.4 months (95% CI, 5.0–33.7). Patients with solitary ICC had significantly longer median OS than patients with multifocal ICC: 25.9 months (95% CI, 20.8–31.0 months) versus 10.7 months (95% CI, 8.0–13.4 months) (P = .02). Patients with progression on the 3-month imaging follow-up had significantly shorter median OS than patients who had stable disease at 3 months: 10.7 months (95% CI, 0.7–20.7 months) versus 37.3 months (95% CI, 16.5–58.1 months) (P = .003). Two (8%) Grade 3 toxicities were reported. ConclusionsFirst-line treatment of ICC with radioembolization showed promising OS and minimal toxicity, especially in patients with solitary tumor. Radioembolization may be considered as a first-line treatment option for unresectable ICC.

The Oncologic Implications of Tumor Multiplicity in Intrahepatic Cholangiocarcinoma: Its Prognostic Value Might Be Underestimated.

In the latest staging system of the American Joint Committee on Cancer for intrahepatic cholangiocarcinoma (IHCCC), solitary tumors with vascular invasion and multiple tumors are grouped together as T2. However, recent studies report that multifocal IHCCC has a worse prognosis than a single lesion. This study aimed to investigate the risk factors for IHCCC and explore the prognostic significance of multiplicity after surgical resection. A total of 257 patients underwent surgery for IHCCC from 2010 to 2019 and the clinicopathological data were retrospectively reviewed. Risk factor analysis was performed to identify variables associated with survival after resection. Survival outcomes were compared between patients with solitary and multiple tumors. In multivariable analysis, the presence of preoperative symptoms, tumor size, lymph node ratio, multiplicity, and tumor differentiation were identified as risk factors for survival. Among 82 patients with T2, overall survival was significantly longer in patients with solitary tumors (sT2) than in those with multiple tumors (mT2) (p=0.017). Survival was compared among patients with stage II-sT2, stage II-mT2, and stage III. The stage II-sT2 group showed prolonged survival when compared with stage II-mT2 or stage III. Survivals of stage II-mT2 and stage III patients were not statistically different. Tumor multiplicity was an independent risk factor for overall survival of IHCCC after surgical resection. Patients with multiple tumors showed poorer survival than patients with a single tumor. The oncologic significance of multiplicity in IHCCC should be reappraised and reflected in the next staging system update.

The oncologic implications of tumor multiplicity in intrahepatic cholangiocarcinoma: Its prognostic value might be underestimated.

611 Background: In the latest staging system of the American Joint Committee on Cancer (AJCC) for intrahepatic cholangiocarcinoma (IHCCC), solitary tumor with vascular invasion and multiple tumors are grouped together as T2. However, recent studies have reported that multifocal IHCCC have worse prognosis than a single lesion. This study aimed to investigate risk factors of IHCCC and to explore the prognostic significance of multiplicity identified by surgical resection. Methods: A total of 277 patients underwent surgery for IHCCC from 2010 to 2019 and the clinicopathological data were retrospectively reviewed. Risk factor analysis was performed to identify variables associated with survival of resected IHCCC. Survival outcomes were compared between patients with solitary tumors and those with multiple tumors. Results: In multivariable analysis, presence of preoperative symptoms, tumor size, lymph node ratio, multiplicity, and tumor differentiation were risk factors for survival. Among 82 patients with T2, overall survival was significantly better in patients with solitary tumors (sT2) than in those with multiple tumors (mT2) (p = 0.017). Survival was compared among patients with stage II-sT2, stage II-mT2, and stage III. Stage II-sT2 group showed prolonged survival than those with stage II-mT2 or stage III. Survival of stage II-mT2 patients was not statistically different from that of stage III patients. Conclusions: Tumor multiplicity was an independent risk factor for overall survival of IHCCC after surgical resection. Patients with multiple tumors showed poorer survival than patients with a single tumor. The oncologic significance of multiplicity in IHCCC should be reappraised and be reflected in the next update of staging system.[Table: see text]

Comparison of Hepatic Arterial Infusion Pump Chemotherapy vs Resection for Patients With Multifocal Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is often multifocal (ie, satellites or intrahepatic metastases) at presentation. To compare the overall survival (OS) of patients with multifocal iCCA after hepatic arterial infusion pump (HAIP) floxuridine chemotherapy vs resection. In this cohort study, patients with histologically confirmed, multifocal iCCA were eligible. The HAIP group consisted of consecutive patients from a single center who underwent HAIP floxuridine chemotherapy for unresectable multifocal iCCA between January 1, 2001, and December 31, 2018. The resection group consisted of consecutive patients from 12 centers who underwent a curative-intent resection for multifocal iCCA between January 1, 1990, and December 31, 2017. Resectable metastatic disease to regional lymph nodes and previous systemic therapy were permitted. Patients with distant metastatic disease (ie, stage IV), those who underwent resection before starting HAIP floxuridine chemotherapy, and those who received a liver transplant were excluded. Data were analyzed on September 1, 2021. Overall survival in the 2 treatment groups was compared using the Kaplan-Meier method and log-rank test. A total of 319 patients with multifocal iCCA were included: 141 in the HAIP group (median [IQR] age, 62 [53-70] years; 79 [56.0%] women) and 178 in the resection group (median [IQR] age, 60 [50-69] years; 91 [51.1%] men). The HAIP group was characterized by a higher percentage of bilobar disease (88.0% [n = 124] vs 34.3% [n = 61]), larger tumors (median, 8.4 cm vs 7.0 cm), and a higher proportion of patients with 4 or more lesions (66.7% [94] vs 24.2% [43]). Postoperative mortality after 30 days was 0.8% (95% CI, 0.0%-2.1%) in the HAIP group vs 6.2% (95% CI, 2.3%-9.7%) in the resection group (P = .01). The median OS for HAIP was 20.3 months vs 18.9 months for resection (P = .32). Five-year OS in patients with 2 or 3 lesions was 23.7% (95% CI, 12.3%-45.7%) in the HAIP group vs 25.7% (95% CI, 17.9%-37.0%) in the resection group. Five-year OS in patients with 4 or more lesions was 5.0% (95% CI, 1.7%-14.3%) in the HAIP group vs 6.8% (95% CI, 1.8%-25.3%) in the resection group. After adjustment for tumor diameter, number of tumors, and lymph node metastases, the hazard ratio of HAIP vs resection was 0.75 (95% CI, 0.55-1.03; P = .07). This cohort study found that patients with multifocal iCCA had similar OS after HAIP floxuridine chemotherapy vs resection. Resection of multifocal intrahepatic cholangiocarcinoma needs to be considered carefully given the complication rate of major liver resection; HAIP floxuridine chemotherapy may be an effective alternative option.

Multifocal Intrahepatic Cholangiocarcinoma and Operative Management of Inoperable Disease

Multifocal Intrahepatic Cholangiocarcinoma and Operative Management of Inoperable Disease

A National Assessment of T2 Staging for Intrahepatic Cholangiocarcinoma and the Poor Prognosis Associated with Multifocality.

T2 intrahepatic cholangiocarcinoma (ICC) isdefined as a solitary tumors with vascular invasion or multifocal tumors including satellite lesions, multiple lesions, and intrahepatic metastases. This study aimed to evaluate the prognosis associated with multifocal tumors. The National Cancer Database was queried from 2004 to 2017 for patients with non-metastatic ICC. The patients were grouped based on T2 staging, multifocality, and lymph node involvement. The study enrolled and classified 4887 patients into clinical (c) stage groups as follows: 15.2% with solitary T2N0 (sT2N0) tumors, 21.3% with multifocal T2N0 (mT2N0) tumors, and 63.5% with node-positive (TxN1) disease. Patients with (c)sT2N0 tumors had higher rates of surgical resection than those with (c)mT2N0 or (c)TxN1 disease (33.5% vs 19.7% vs 15.0%; p < 0.01). Median overall survival (OS) was better for the patients with (c)sT2N0 tumors than for those with multifocal and node-positive disease (15.4 vs 10.4 vs 10.4 months; p < 0.01). Onmultivariate analysis, (c)sT2N0 tumors were associated with better OS than (c)mT2N0 tumors [hazard ratio (HR), 1.31; 95% confidence interval (CI), 1.17-1.46; p < 0.01] or (c)TxN1 disease (HR,1.41; 95% CI 1.28-1.56; p < 0.01). In a subset analysis based on pathologic (p) staging of patients who underwent surgical resection with regional lymphadenectomy, multivariate analysis demonstrated that (p)sT2N0 tumors were associated with better OS than (p)mT2N0 tumors (HR,1.40; 95% CI 1.03-1.92; p = 0.03) or (p)TxN1 disease (HR, 2.05; 95% CI 1.62-2.58; p < 0.01). Multifocal T2N0 ICC is associated with poor OS and has a disparate prognosis compared with solitary T2N0 disease, even among patients who undergo resection. Future staging criteria should account for the poor outcomes associated with multifocal ICC.

HELIX-ICC: An-open label phase II trial of induction systemic mFOLFIRINOX followed by concurrent hepatic arterial infusion of floxuridine and systemic mFOLFIRI for unresectable intrahepatic cholangiocarcinoma.

TPS500 Background: The majority of patients with intrahepatic cholangiocarcinoma (ICC) present with advanced liver dominant disease rendering them unresectable. The current standard of care supports palliative treatment of unresectable ICC with gemcitabine plus cisplatin. Alternatively, continuous liver-directed therapy using a surgically implanted hepatic arterial infusion (HAI) pump allows for maximal treatment of liver tumors with limited systemic side-effects and can facilitate conversion to a resectable status. No prospective clinical trial has utilized FOLFIRINOX in combination with HAI floxuridine-dexamethasone for ICC. Methods: HELIX-ICC is a first-line, single-center, single-arm, phase II clinical trial enrolling patients with liver-dominant unresectable or multifocal ICC. Only patients with microsatellite stable cancer and no prior liver radiotherapy will be included. Patients are administered dose-modified FOLFIRINOX systemically for 4 cycles over 8 weeks. Those with evidence of disease control on restaging imaging and laparoscopy will proceed to HAI pump placement. Treatment continues with two 28-day cycles of combined HAI floxuridine (1.08 mg/kg) with dexamethasone for 14 days and systemic dose-modified FOLFIRI starting on day 15. The primary objectives are to evaluate the safety and efficacy (disease control rate [DCR] at 6 months) of this novel treatment approach that utilizes our institutional dose-reduced HAI floxuridine protocol in combination with modified systemic regimens to facilitate control of liver disease and maximize patient quality of life (QoL). HELIX-ICC includes many exploratory analyses through longitudinal collection of blood samples, liver biopsies (including an end of trial research biopsy), and QoL metrics (Table). The study is open to n = 30 with an initial safety run-in of 6 patients, of which 4 have enrolled at the time of submission. This study is designed to allow for drop out of 9 patients, with total accrual of 21 patients to protocol completion achieving 80.2% power at 0.05 significance to detect a 25% increase in DCR at 6 months. Clinical trial information: NCT04251715. [Table: see text]

Should Multifocal Intrahepatic Cholangiocarcinoma Be Considered as Metastasis in Surgically Resected Patients?

Introduction: Surgical resection is the main treatment for intrahepatic cholangiocarcinoma (ICC). The presence of multifocal lesions is one of the poor prognostic factors. This study aimed to investigate the overall survival of multifocal ICC in surgically resected patients.

Multiomic Analysis Reveals Comprehensive Tumor Heterogeneity and Distinct Immune Subtypes in Multifocal Intrahepatic Cholangiocarcinoma.

Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma (ICC). However, little is known about the intertumor heterogeneity (ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making. We obtained 66 tumor samples from 16 patients with multifocal ICC and characterized the tumor and immune heterogeneity using whole-exome sequencing, bulk and single-cell RNA sequencing, methylation microarray, and multiplex immunostaining. Patients were divided into high- or low-ITH groups according to the median ITH index. Two independent cohorts were used to validate findings. Responses to anti-PD-1 therapy were assessed. Multifocal ICC presented considerable intertumor genomic, transcriptional, and epigenomic heterogeneity within a patient in high ITH group. The immune profile among multiple tumors within a patient was relatively less heterogeneous in high- or low-ITH group, and consistent responses of multiple tumors to anti-PD-1 immunotherapy were observed. Unsupervised clustering of immune markers identified one low and one high immune subtype, with higher immune cell infiltration, closer tumor-immune cell interactions, and upregulated IFN-signature expression in high-immune subtype. Determining expression levels of CD8B and ICOS facilitated this immune classification and prediction of patient prognosis. Finally, promoter DNA methylation contributed to different immune profiles of two subtypes by regulating immune-gene expression. There is comprehensive heterogeneity in the genome, transcriptome, and epigenome of multifocal ICC. On the basis of the less heterogeneous immune profile of ICC, we suggest an immune classification that stratifies patients' prognosis and may support personalized immunotherapy.

Primary tumor resection improves survival in patients with multifocal intrahepatic cholangiocarcinoma based on a population study

The purpose of our study was to evaluate the effect of surgery on the survival and prognosis of patients with multifocal intrahepatic cholangiocarcinoma (ICCA). Patients with multifocal ICCA were selected from the SEER (Surveillance, Epidemiology, and End Results) database between 2010 and 2016. Kaplan–Meier analyses and log-rank tests were used to evaluate the difference in survival between the surgery group and the non-surgery group. We applied the Cox proportional hazards regression model to identify prognostic factors of overall survival (OS) and cancer-specific survival (CSS). In total, 580 patients were enrolled in our study, including 151 patients who underwent surgery and 429 patients who did not. The median survival time of surgical patients was longer than non-surgical patients (OS: 25 months vs. 8 months, p < 0.001; CSS: 40 months vs. 25 months, p < 0.001). Similarly, the 5-year survival rate in the surgery group was significantly higher than those in the non-surgery group (5-year OS rate: 12.91% vs. 0%; p < 0.001; 5-year CSS rate:26.91% vs. 0%; p < 0.001). Multivariate Cox analysis showed that the OS (HR:0.299, 95% CI: 0.229–0.390, p < 0.001) and CSS (HR:0.305, 95% CI:0.222–0.419, p < 0.001) of patients undergoing surgical resection were significantly improved. Meanwhile, after propensity score matching (PSM) of the original data, we come to the same conclusion.

Genomic profiling of multifocal intrahepatic cholangiocarcinoma reveals intraindividual concordance of genetic alterations.

In multifocal intrahepatic cholangiocarcinoma (IHC), intrahepatic metastases (IM) represent a contraindication to surgical resection, whereas satellite nodules (SN) do not. However, no consensus criteria exist to distinguish IM from SN. The purpose of this study was to determine genetic alterations and clonal relationships in surgically resected multifocal IHC. Next-generation sequencing of 34 spatially separated IHC tumors was performed using a targeted panel of 201 cancer-associated genes. Proposed definitions in the literature were applied of SN located in the same liver segment and ≤2 cm from the primary tumor; and IM located in a different liver segment and/or >2 cm from the primary tumor. Somatic point mutations concordant across tumors from individual patients included BAP1, SMARCA4 and IDH1. Small insertions and deletions (indels) present at the same genome positions among all tumors from individuals included indels in DNA repair genes, CHEK1, ERCC5, ATR and MSH6. Copy number alterations were also similar between all tumors in each patient. In this cohort of multifocal IHC, genomic profiles were concordant across all tumors in each patient, suggesting a common progenitor cell origin, regardless of the location of tumors in the liver. The decision to perform surgery should not be based upon a perceived distinction between IM and SN.

Reappraisal of the T Category for Solitary Intrahepatic Cholangiocarcinoma by Tumor Size in 611 Early-Stage (T1-2N0M0) Patients After Hepatectomy: a Surveillance, Epidemiology, and End Results (SEER) Analysis

BackgroundThe association between tumor size and survival in patients with intrahepatic cholangiocarcinoma (ICC) after hepatectomy is controversial, and the T category in the American Joint Committee on Cancer (AJCC) stage for ICC is a topic of debate. MethodsData from 611 T1-2N0M0 ICC patients classified by the AJCC 8th edition who underwent hepatectomy were extracted from the Surveillance, Epidemiology, and End Results (SEER) database during 1988–2015. Cancer-specific survival was evaluated using Kaplan-Meier analysis. The optimal cutoff value of solitary tumor size was used an adjusted p value approach to discriminating patient survival. ResultsIn the AJCC 8th staging system, using a 5-cm cut-off value of tumor size for solitary ICC without vascular invasion (S/VI–) was not associated with survival in T1 category (p = 0.201), and multifocal ICC with vascular invasion had a worse survival than solitary ICC with vascular invasion (S/VI+) in T2 category (p = 0.014). Tumor size was a prognostic factor for both S/VI– and S/VI+, the optimal cutoff value of tumor size was obtained 8 cm for S/VI– and 3 cm for S/VI+. S/VI– ≤ 8 cm had a similar survival to S/VI+ ≤ 3 cm (p = 0.126), S/VI– > 8 cm had a similar survival to S/VI+ > 3 cm (p = 0.655), and multifocal ICC had a similar survival with S/VI– > 8 cm (p = 0.159) and S/VI+ > 3 cm (p = 0.196). When the cohort was divided into two groups—new T1 (S/VI– ≤ 8 cm and S/VI+ ≤ 3 cm) and new T2 (S/VI– > 8 cm, S/VI+ > 3 cm and multifocal ICC)—significant survival difference was observed (p < 0.0001). ConclusionsThe discriminatory power of the AJCC 8th edition for solitary ICC could be further enhanced by subdividing tumors according to size and vascular invasion (8 cm for S/VI– and 3 cm for S/VI+).

Long-term survival following resection of multifocal Intrahepatic Cholangiocarcinoma

Background: Surgical resection is the best curative treatment option for patients with solitary intrahepatic cholangiocarcinoma (sIHCC). Multiple tumours in intra-hepatic cholangiocarcinoma (mIHCC) could be indicative of a multifocal primary or an index lesion with intrahepatic metastases (satellite lesions). The current study is aimed to assess the overall survival following liver resection between sIHCC and mIHCC after surgical resection. Material & Methods: Patients who underwent liver resection for IHCC between 2004 and 2014 were included from a prospectively maintained database at a tertiary referral centre. Univariable analyses were performed to identify predictors of overall survival (OS). All analyses were performed using IBM SPSS 19 (IBM Corp. Armonk, NY), with p<0.05 being statistically significant. Results: An total of 102 resections were included. Data about the number of lesions were available for 81(79%) patients. 51(63%) had a liver resection for sIHCC and 30 (37%) for a mIHCC. The number of mass-forming subtype lesions were significantly higher in the sIHCC (p 0.002) and the Grade 3-4 in the mIHCC respectively. Size of the lesion was not significantly different between the two groups (p=0.10). Median OS was 28 months (95%CI 8 – 47 months) and 9 months (95%CI 5– 12 months) in the sIHCC and mIHCC groups (p<0·0001) with 1-year survival of 23% in the sIHCC and 10% in the mIHCC groups (HR: 3.0:95%CI 1.6-6.2; p<0.001). Conclusion(s): mIHCC demonstrate aggressive behaviour with higher-grade disease and worse long-term survival compared to sIHCC.

Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma

Background: Bilobar lesions and multiple tumor foci of intrahepatic cholangiocarcinoma (ICC) are often considered a contra-indication for resection. We sought to define long-term outcomes in this subset of patients. Methods: Patients who underwent resection for ICC between 1990 and 2015 were identified from 12 major HPB centers. Outcomes of patients with solitary and multiple tumors were compared. Satellite lesions, small lesions within 1 cm from the index tumor or within the same segment of a larger lesion, were not defined as multiple tumors. Multivariable regression analysis was used to assess survival. Results: 1,023 patients underwent a curative-intent resection of ICC. On final pathology, 235 patients (23.0%) had multiple tumors. Patients with multiple tumors had a median of 2 tumors (interquartile range [IQR]: 2–3). Recurrence occurred in 416 (52.8%) patients with a solitary tumor versus 135 (57.4%) patients with multiple tumors (p = 0.209). Median survival of patients with a solitary tumor was 42.6 months (95%CI: 35.9–49.4), while the median survival of patients with multiple tumors was 26.9 months (p < 0.001) One-, 3-, and 5-year survival of patients with multiple tumors were 75.1%, 40.4% and 25.6% respectively. In multivariable analysis, positive resection margin (Hazard Ratio [HR]: 1.57; p = 0.001), lymph node metastasis (HR:1.84; p < 0.001), invasion of adjacent organs (HR: 2.02; p < 0.001), and tumor size (per centimeter increase) (HR: 1.06, p < 0.001) were each associated with an increased hazard of death. In contrast, presence of multiple tumors was not an independent prognostic factor of survival (HR: 0.943, 95%CI: 0.87–1.32; p = 0.506). Conclusion: Five-year survival after complete resection of patients with multiple ICC was 25.6%. Multi-focal ICC should not be considered an absolute surgical contra-indication and may provide a benefit in a subset patients.

The Limitations of Standard Clinicopathologic Features to Accurately Risk-Stratify Prognosis after Resection of Intrahepatic Cholangiocarcinoma

BackgroundThe ability to provide accurate prognostic data after hepatectomy for intrahepatic cholangiocarcinoma (ICC) remains poor. We sought to develop and validate a nomogram to predict survival, as well as investigate the clinical implications of underestimating patients’ risk of recurrence. MethodsPatients undergoing curative-intent resection of ICC between 1990 and 2015 at 14 major hepatobiliary centers were included. Variables significant on multivariable analysis were used to construct a nomogram to predict disease-free survival (DFS). The nomogram assigned a score to each variable included in the model and calculated the risk of recurrence. ResultsEight hundred ninety-seven patients are included in the analytic cohort. On multivariable Cox regression analysis, tumor size > 5 cm (HR 1.98, 95% CI 1.44–2.13; p < 0.001), multifocal ICC (HR 1.64, 95% CI 1.32–2.03; p < 0.001), lymph node metastasis (HR 1.63, 95% CI 1.25–2.11; p < 0.001), poorly differentiated tumor grade (HR 1.50, 95% CI 1.21–1.89; p < 0.001), and periductal infiltrating type (PI) morphology (HR 1.42, 95% CI 1.09–1.83; p = 0.008) were independent adverse risk factors associated with decreased DFS. The Harrell’s c-index for the nomogram was 0.633 (with n = 5000 bootstrapping resamples) and the plot comparing predicted and actuarial DFS demonstrated a good calibration of the model. A subset of patients (n = 282) had a DFS worse than predicted (ΔPredicted DFS − Actuarial DFS > 6 months). Moreover, underestimation of a recurrence risk was more common among patients with clinicopathologic features traditionally considered “favorable.” ConclusionA nomogram based on standard clinicopathologic characteristics was suboptimal in its ability to predict accurately risk of recurrence among patients with ICC after curative-intent liver resection. Particularly, the risk of underestimating patient risk of recurrence was highest among patients with historically favorable characteristics. Over one third of patients recurred > 6 months earlier than the DFS predicted by the nomogram.

Development and Validation of a Prognostic Score for Intrahepatic Cholangiocarcinoma

In patients with intrahepatic cholangiocarcinoma (ICC), the oncologic benefit of surgery and perioperative outcomes for large multifocal tumors or tumors with contiguous organ involvement remain to be defined. To develop and externally validate a simplified prognostic score for ICC and to determine perioperative outcomes for large multifocal ICCs or tumors with contiguous organ involvement. This study of a contemporary cohort merged data from the California Cancer Registry (January 1, 2004, through December 31, 2011) and the Office of Statewide Health Planning and Development inpatient database. Clinicopathologic variables were compared between tumors that were intrahepatic, small (<7 cm), and solitary (ISS) and those that had extrahepatic extension and were large (≥7 cm) and multifocal (ELM). External validation of the prognostic model was performed using an independent data set from the National Cancer Institute's Surveillance, Epidemiology, and End Results database from January 1, 2004, through December 31, 2013. Patient overall survival after hepatectomy. A total of 275 patients (123 men [44.7%] and 152 women [55.3%]; median [interquartile range] age, 65 [55-72] years) met the inclusion criteria. No significant differences in overall complication rate (ISS, 48 [34.5%]; ELM, 37 [27.2%]; P = .19) and mortality rate (ISS, 10 [7.2%]; ELM, 6 [4.4%]; P = .32) were found. A multivariate Cox proportional hazards model demonstrated that multifocality, extrahepatic extension, grade, node positivity, and age greater than 60 years are independently associated with worse overall survival. These variables were used to develop the MEGNA prognostic score. The prognostic separation/discrimination index was improved with the MEGNA prognostic score (0.21; 95% CI, 0.11-0.33) compared with the staging systems of the American Joint Committee on Cancer sixth (0.17; 95% CI, 0.09-0.29) and seventh (0.18; 95% CI, 0.08-0.30) editions. The MEGNA prognostic score allows more accurate and superior estimation of patient survival after hepatectomy compared with current staging systems.

Defining when to offer operative treatment for intrahepatic cholangiocarcinoma: A regret-based decision curves analysis

Regret-based decision curve analysis (DCA) is a framework that assesses the medical decision process according to physician attitudes (expected regret) relative to disease-based factors. We sought to apply this methodology to decisions around the operative management of intrahepatic cholangiocarcinoma (ICC). Utilizing a multicentric database of 799 patients who underwent liver resection for ICC, we developed a prognostic nomogram. DCA tested 3 strategies: (1) perform an operation on all patients, (2) never perform an operation, and (3) use the nomogram to select patients for an operation. Four preoperative variables were included in the nomogram: major vascular invasion (HR=1.36), tumor number (multifocal, HR=1.18), tumor size (>5cm, HR=1.45), and suspicious lymph nodes on imaging (HR=1.47; all P<.05). The regret-DCA was assessed using an online survey of 50 physicians, expert in the treatment of ICC. For a patient with a multifocal ICC, largest lesion measuring >5cm, one suspicious malignant lymph node, and vascular invasion on imaging, the 1-year predicted survival was 52% according to the nomogram. Based on the therapeutic decision of the regret-DCA, 60% of physicians would advise against an operation for this scenario. Conversely, all physicians recommended an operation to a patient with an early ICC (single nodule measuring 3cm, no suspicious lymph nodes, and no vascular invasion at imaging). By integrating a nomogram based on preoperative variables and a regret-based DCA, we were able to define the elements of how decisions rely on medical knowledge (postoperative survival predicted by a nomogram, severity disease assessment) and physician attitudes (regret of commission and omission).

Liver Resection for Advanced Intrahepatic Cholangiocarcinoma: A Cost-Utility Analysis.

Data on cost-effectiveness and efficacy of hepatic resection (HR) for advanced intrahepatic cholangiocarcinoma (ICC) are lacking. We sought to estimate the cost-effectiveness of upfront HR resulting in an R1 resection (strategy A) relative to initial systemic chemotherapy (sCT) followed by possible curative HR (strategy B) for patients with advanced ICC. A Markov model was developed using data from a systematic literature review. Three base cases were considered: (1) ICC >6 cm (2) ICC with vascular invasion (3) multi-focal ICC. A Monte Carlo simulation assessed outcomes including quality-adjusted life months (QALMs) and incremental cost-effectiveness ratio (ICER). The net health benefit (NHB) of strategy A versus strategy B was 1.4 QALMs for ICC >6 cm and 1.3 QALMs for ICC and vascular invasion; in contrast, there was a negative NHB for HR versus sCT for multi-focal ICC (-0.3 QALMs). In single nodule ICC >6 cm, the ICER of HR versus sCT was $22,482/quality-adjusted life years (QALY) and the ICER of HR versus sCT was $20,953/QALY for ICC with vascular invasion. In multi-focal ICC, the ICER of HR compared with sCT was $83,604/QALY. Patients with a higher American Society of Anesthesiologists score (coefficient 0.94), male sex (coefficient 0.43), low quality of life after sCT (coefficient -2.57) and T3 tumors (coefficient 0.53) had a better NHB for HR relative to sCT followed by potential surgery. For patients with large ICC or ICC and vascular invasion, HR was more cost-effective than sCT. In contrast, HR was not associated with a positive NHB relative to sCT for patients with multi-focal ICC, and therefore these patients should be treated with sCT rather than HR.