Unresectable Cholangiocarcinoma Research Articles

Durvalumab-Induced Immune Thrombocytopenia in Patients with Advanced Cholangiocarcinoma Undergoing Yttrium-90 Radioembolization

Introduction: Immune thrombocytopenia (ITP) secondary to durvalumab, a programmed cell death ligand 1 inhibitor, is a rare but clinically significant immune-related adverse event. Herein, we present 2 patients with cholangiocarcinoma who developed ITP immediately post-yttrium-90 radioembolization (Y90-RE) while on durvalumab-based systemic therapy. We hypothesize that given the timing, the immunotherapy and the radioembolization combination led to this event. It is not uncommon given the approval of immunotherapy and its role in locoregional therapies, that patients are treated with a combination of systemic immunotherapy and radioembolization or other forms of radiation, thus signifying the importance of potential complications. Case Presentation: Two patients, a 67-year-old female and a 60-year-old man, with biopsy-proven advanced unresectable cholangiocarcinoma, received a combination of systemic therapy with durvalumab, gemcitabine, and cisplatin and subsequently Y90-RE. Both patients developed ITP following in the immediate post-Y90-RE period. All other causes of ITP were comprehensively ruled out and treatment for ITP was initiated in the form of high-dose steroid and intravenous immunoglobulins. Durvalumab was discontinued, and only gemcitabine/cisplatin-based chemotherapy was continued thereafter. Due to recurrence, one of the patients required longer courses of steroids as well as thrombopoietin receptor agonists. Conclusion: Immunotherapy in the form of durvalumab and now pembrolizumab alongside chemotherapy is an approved first-line standard of care. Furthermore, it is not uncommon for patients to receive Y90-RE to improve patient outcomes. This report highlights the development of ITP in 2 patients who received durvalumab alongside Y90-RE. Awareness of this as a potential immune-mediated event is important to allow for close monitoring of platelet counts and for early intervention/management when this occurs.

Effect of photodynamic therapy on peripheral immune system for unresectable cholangiocarcinoma

BackgroundPhotodynamic therapy (PDT) has been emerging as a promising treatment for unresectable cholangiocarcinoma (CCA). A number of experiments have demonstrated that PDT could enhance antitumor immunity significantly. However, the impact of PDT on peripheral immune system for unresectable CCA remains unclear. MethodsIn a clinical trial comparing the perioperative and long-term outcomes of PDT+stent treatment and stent alone treatment for unresectable CCA, we tested the levels of lymphocytes (CD4+ T cells, CD8+ T cells, NK cells, B cells and Treg cells) and immune-related cytokines (IL-4, IL-6, IL-10, TNF-α, TGF-β, perforin, GM-CSF and IFN-γ) in peripheral blood before and after PDT+stent treatment or stent alone treatment and analyzed the influence of PDT on peripheral immune system for unresectable CCA. ResultsBefore treatment, the levels of all the immune cells and immune-related cytokines did not show significant differences between the PDT+stent group and stent alone group. The ratio of CD8+ T cells increased significantly after PDT treatment, but other kinds of lymphocytes did not show significant difference. Increased level of IL-6 and decreased level of perforin and TGF-β after PDT treatment were demonstrated, whereas no significant changes were found for other immune-related cytokines. ConclusionPDT altered the levels of immune cells and immune-related cytokines in the peripheral blood of unresectable CCA patients, potentially correlating with the therapeutic efficacy of PDT in unresectable CCA treatment. Future studies could delve deeper into this aspect to explore how PDT can be more effectively utilized in the management of unresectable CCA.

The Impact of Radiofrequency Ablation on Survival Outcomes and Stent Patency in Patients with Unresectable Cholangiocarcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Endoluminal biliary radiofrequency ablation (RFA) has been proposed as a palliative treatment for patients with malignant biliary obstruction (MBO) in order to improve stent patency and survival. However, the existing data on patients with inoperable extrahepatic cholangiocarcinoma (eCCA) are conflicting. We performed a meta-analysis of randomized trials comparing RFA plus stenting versus stenting alone in patients with inoperable eCCA. We searched for trials published in the PubMed/MEDLINE, Scopus, and Cochrane databases up to November 2023. Data extraction was conducted from published studies, and a quality assessment was carried out in accordance with the guidelines recommended by the Cochrane Collaboration. Hazard ratios (HRs) with 95% CI were estimated from the trials. The primary endpoints of interest were overall survival and stent patency. Out of 275 results, 5 randomized trials and 370 patients were included. While overall survival was not different between the groups (HR 0.62; 95% CI 0.36-1.07; p = 0.09; I2 = 80%;), the subgroup analysis of studies employing plastic stents showed a trend toward better survival in the RFA-treated group (HR 0.42; 95% CI 0.22-0.80; p = 0.009; I2 = 72%). Stent patency was improved in patients receiving RFA (HR 0.64; 95% CI 0.45-0.90; p = 0.01; I2 = 23%). Adverse events were not different between the groups (OR 1.21; 95% CI 0.69-2.12; p = 0.50; I2 = 0%). Despite the promising results, high heterogeneity and potential biases in the included studies suggest the need for further high-quality randomized trials to explore the potential cumulative effects of RFA on CCA treatment outcomes.

Single-institutional analysis of radiotherapy and orthotopic liver transplant for patients with unresectable cholangiocarcinoma.

466 Background: There is increasing interest in effective strategies for locoregional therapy for cholangiocarcinoma, particularly given the evolving role of orthotopic liver transplant (OLT) for select patients. This single-institution retrospective study compares the clinical efficacy and toxicity of stereotactic body radiotherapy (SBRT), conventional fractionation chemoradiation (CRT), or SBRT as a bridge to OLT in patients with unresectable early stage and locally advanced cholangiocarcinoma. Methods: We reviewed a total of 31 patients from 2010 to 2023 with intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and perihilar cholangiocarcinoma who were treated with SBRT (n=22) or CRT (n=9). SBRT was delivered in 1-5 fractions, median dose of 40 Gy, and dose ranging from 16 Gy to 60 Gy. CRT was delivered in 13-28 fractions, median dose of 50.2 Gy, and dose ranging from 45 Gy to 52.5 Gy. Kaplan-Meier was used to analyze overall survival (OS), progression-free survival (PFS), and local control (LC). Acute and late G3+ toxicity was scored using CTCAE, version 5.0. Results: We identified 13 patients with ICC, 5 with ECC, and 13 with perihilar disease where SBRT or CRT was part of upfront definitive treatment. With a median follow-up time of 11 months, there was no statistical difference between SBRT vs. CRT for OS (median 21 vs. 22 months; p=0.36), PFS (median 14.2 vs. 11 months; p=0.09), and 1-year LC (73.2% vs. 66.7%; p=0.10). However, SBRT appeared to have lower proportions of acute grade 3+ (9.1% vs. 33.3%) and chronic grade 3+ toxicities (22.7% vs. 33.3%). Four patients with early stage perihilar or ICC underwent SBRT as successful bridge to transplant, with no evidence of disease progression at 5.4 months. An additional 2 out of 8 patients were removed from protocol due to disease progression and 2 others remain on protocol, awaiting OLT. Conclusions: In our series of unresectable cholangiocarcinoma, we found no difference in OS, PFS, and LC for patients treated with SBRT vs. CRT, although the former appeared to have lower toxicity and a trend towards improved PFS. Further research is needed to compare SBRT and CRT as definitive treatment or bridge to OLT for patients with unresectable cholangiocarcinoma.

Salvage hepatic artery infusion chemotherapy after first-line systemic failure in patients with unresectable cholangiocarcinoma.

522 Background: Unresectable intrahepatic cholangiocarcinoma (IHC) is associated with poor overall survival (OS). Prior studies have suggested improved outcomes with hepatic artery infusion chemotherapy (HAIC), with or without systemic (SYS) compared to SYS alone, but the role of HAIC continues to evolve. This study compares outcome of HAIC when used as 1st line treatment compared to 2nd line therapy in patients with advanced IHC. Methods: In this retrospective review, 722 consecutive biopsy-proven, liver limited IHC were evaluated from 2000-2018. Patients undergoing upfront surgery or those with metastatic disease beyond regional lymph nodes were excluded. Overall survival (OS) was estimated using Kaplan-Meier methods. Cox regression model was used to examine the association of HAIC given at any time point with OS. To further dissect the timing of HAIC therapy (1st vs 2nd line) on OS, multi-state models using parametric Cox regression, as well as separate Cause-specific hazard model to intergrade the transition to 2nd line HAIC from the 1st line SYS state were used to estimate the mean survival time from diagnosis. Results: 336 patients eligible for HAIC were analyzed: 137 patients began treatment with 1st line HAIC (median age 63, 40% male) and 199 patients received 1st line SYS (median age 64, 46% male). Median time to first treatment initiation was 1.8 vs 1.2 months for 1st line HAIC and SYS, respectively. Median OS of all patients was 22 months (95% CI: 20-25 months), and HAIC given at any time was associated with reduced all-cause mortality by 34% (HR: 0.66, 95%CI: 0.52-0.84). Multi-states analyses revealed that patients who received 1st line HAIC had a mean OS of 33 months from disease diagnosis. Patients who transitioned to 2nd line HAIC after 1st line SYS had a mean OS of 36 months from diagnosis, while those who failed 1st line SYS and continued 2nd line SYS had a mean OS of 22 months from diagnosis. Patients who received no further treatment after 1st line SYS had a mean OS of 9 months. Median OS from the start of 2nd line for patients who received 2nd line HAIC was 18 months and 8 months for patients who started 2nd line SYS therapy. The sites of progression of disease (POD) in different treatment groups has been described in the Table. Conclusions: HAIC treatment of unresectable liver-dominant IHC at any time was associated with reduced mortality by 34%. Mean OS in patients treated with 2nd line HAIC did not appear to be significantly different than those receiving HAIC as 1st line therapy and both appeared to be superior to 2nd line SYS. The survival benefits of HAIC appear to be maintained after failure of 1st line systemic chemotherapy. [Table: see text]

Expanding immunotherapy options in cholangiocarcinoma: Role of CD27 agonist in combination with PD-L1 and MEK inhibition on antitumor effect and CD8+ T cells.

518 Background: Despite addition of PD-L1 therapy to unresectable cholangiocarcinoma (CCA) standard of care, there remains an unmet need for novel therapies. Our recent phase II trial of dual PD-L1 inhibition (PD-L1i) and MEK inhibition (MEKi) significantly improved progression-free survival (PFS). While MEKi enhances tumor antigen presentation and T cell tumor infiltration, it also impairs T cell priming and activation with notable CD27 upregulation. Our work reveals that CD27 agonists (CD27Ag) foster T cell stem-like and resident memory phenotypes, negating inhibitory effect of MEKi on CD8+ T cells. We hypothesized that addition of a CD27Ag to PD-L1i/MEKi combination therapy would rescue T cell activation and improve antitumor efficacy. Methods: Immune cells from pmel-1 mice were isolated, activated with gp100, and cultured in vitro with 100 IU/mL IL-2 and single, dual, or triple therapy with CD27Ag, cobimetinib (MEKi) and/or αPD-L1. Day 3 flow cytometry characterized CD8+ T cell phenotype and cytokine expression. Additionally, syngeneic murine CCA cell line URCCA4.3 (KrasG21D, tp53-/-) was injected into C57BL/6 mice, subcutaneously or intrahepatic, followed by ~3 weeks of treatment with mono, dual, or triple therapy. For CD8 depletion studies, CD8-depleting antibody was given on the day prior to and following surgery and every 3-4 days afterwards. Tumor and tumor-draining lymph nodes were harvested at study endpoint. Lymphocytes were characterized by flow cytometry. Results: MEKi, alone or with αPD-L1, reduced frequency of activated T cells in vitro (dose-dependent effect on CD69+). CD27Ag combined with MEKi maintained prominent T cell activation. Triple therapy PD-L1i/MEKi/CD27Ag significantly reduced tumor growth rate in mice versus mono or dual therapies (p<0.05). Tumor-infiltrating lymphocytes comprised a stem-like (Tcf-1+), effector memory (CD44+CD62L-), and tissue resident memory (CD103+CD69+) phenotype in triple therapy versus single or dual therapy (p<0.01, p<0.0001, p<0.0001 respectively). All groups had similar numbers of CD8+ stem-like cells (Tcf-1+Tim-3-) in draining lymph nodes, but these cells were only present in tumor from the triple therapy arm (p<0.05). Cell depletion studies showed that CD8+ T cells were required for efficacy of triple therapy in vivo. Finally, an aggressive orthotopic liver tumor model showed improved median survival in triple therapy mice versus control (37.5 days versus 29.5 days, p<0.01). Conclusions: CD27 agonism prevents the impairment of T cell activation that was mediated by MEKi. Moreover, this CD27Ag/MEKi/PDL1i triple therapy bolstered trafficking of T cells with stem-like, effector, or resident memory properties, in turn enhancing the antitumor response. This therapy is being evaluated in metastatic CCA patients in an ongoing Phase II clinical trial.

ХИМИОТЕРАПИЯ НЕОПЕРАБЕЛЬНОГО РАКА ЖЕЛЧЕВЫВОДЯЩИХ ПРОТОКОВ. ОБЗОР

Malignant tumors of the biliary ducts (BDC, biliary duct cancer) are rare cancers arising from the epithelium of the extrahepatic biliary tract, including intrahepatic and extrahepatic cholangiocarcinomas, as well as malignant tumors of the gallbladder and ampullae of the big duodenal papilla (BDP). The global and Russian incidence of these diseases is <1% of all cancer cases. Despite their rarity, BDC has one of the lowest five-year survival rates, second only to pancreatic head tumors. The lack of early symptoms leads to late diagnosis, with 80% of patients presenting with unresectable BDC or advanced disease, significantly impacting life expectancy and quality of life. Unresectable cholangiocarcinoma is primarily treated with chemotherapy, including systemic, targeted, and local invasive methods. However, obstructive jaundice and hepatorenal failure limit the use of aggressive chemotherapy in most patients, hindering the implementation of effective systemic protocols. While targeted chemotherapy shows promise due to the abundance of molecular targets in bile duct malignancies, its impact on complications is limited. Local chemotherapy directly affects tumor size, invasion, and bile duct lumen, but its clinical effectiveness and impact on overall survival remain inconclusive. The search for new local and systemic approaches to cholangiocarcinoma is promising, aiming to improve overall survival and address obstructive jaundice.

Single center experience using stereotactic body radiation therapy (SBRT) on orthotopic liver transplant protocol for unresectable cholangiocarcinoma

PurposeTo evaluate tolerability, pathologic response, and disease outcomes utilizing pre-operative stereotactic body radiation therapy (SBRT) followed by consolidation chemotherapy (CHT) prior to orthotopic liver transplant (OLT) in unresectable cholangiocarcinoma (CCA). MethodsThis was a retrospective chart review of patients treated on OLT protocol at a single tertiary center from 2012 to 2019. Patients received pre-operative SBRT (40–50 Gy in 5 fractions) followed by CHT until progression or OLT. Progression-free survival (PFS) and overall survival (OS) were compared via log-rank test and Cox proportional hazards regression. Results26 patients (84.6% hilar, 15.4% intrahepatic) were identified for analysis. Eight patients (30.8%) patients developed acute toxicity after SBRT, mostly grade 1 nausea. Nine (34.6%) patients underwent OLT of which 4 (44.4%) achieved a pathologic complete response (pCR). Five (55.6%) OLT patients, including 2 pCR, developed recurrence at a median time of 49.9 weeks after OLT. 3-year OS for the OLT and dropout cohort was 75% and 9%, respectively (p < 0.0001). OS in hilar tumors only was statistically different for those that achieved a pCR (p = 0.014). ConclusionsPre-operative SBRT is a well-tolerated and effective radiation technique as part of OLT protocol for unresectable CCA and conferred in a pCR rate of 44% within our cohort.

COVID-19 induced remission of biliary and renal cell carcinomas.

e14598 Background: Clear cell renal carcinoma and cholangiocarcinoma are resistant to standard therapy. Complete remissions are rare. SARS-CoV-2 (COVID-19) boosts anti-viral immune responses but effects on cancers are unknown. Case reports of hematologic cancer remissions after COVID infection are emerging. Anti PD1/PD-L1 antibody therapy have prolonged remission in 20% of solid tumor patients. mRNA COVID-19 vaccines and COVID-19 active infections create anti-viral immune responses - increased IgG titers, SARS-CoV-2-specific antibodies, and boost T-cell response. Anti PD-1/PD-L1 antibodies immune responses, are presumed independent of the immune response to COVID vaccination/infection. Two previous case reports of hematologic remission were seen after COVID infection. (Hodgkins, multiple myeloma). There are no cases of solid cancer remission after COVID-19 exposure. Methods: Three patients with solid cancers and complete/near complete radiographic remissions after COVID-19 exposure. Two on low carbohydrate diets. History, dietary course and clinical outcomes are presented. Results: Case 1: 58 year old male diagnosed with stage IV clear cell renal carcinoma (lung nodules, mediastinal nodes). After 5 years he progressed on Sunitinib and began Nivolumab. His cancer stabilized but hypophysitis, diarrhea, severe jaw pain ended his treatment. After COVID-19 booster vaccine, he became anorexic, lost 50 lbs over 8 weeks (267 to 211 lb). Relapse was suspected but PET CT showed complete resolution of his lung nodules and adenopathy. Asymptomatic and in remission over 9 months post vaccine. Case 2: 51 year old male heavily pretreated stage 4 renal cell cancer, bone, liver, nodal metastases. On Nivolumab with stable disease but after COVID booster vaccine had high fever, fatigue, myalgia. PET CT scans later showed near complete resolution of his bony, hepatic and nodal metastatic sites. Case 3: 75 year old male with unresectable cholangiocarcinoma on second line Atezolizumab. COVID-19 infection was followed by complete radiographic remission. Conclusions: Effects of SARS-CoV-2 (COVID-19) on cancers remain unknown. Few case reports of cancer remissions after infections are emerging. These are two cases of renal cell cancers in complete remission after COVID-19 vaccination while on immunotherapy. Both followed low glycemic diets. Third case was a complete remission of biliary cancer after an acute COVID-19 infection. Proposed anti-cancer mechanisms - pathogen specific T cell action, anti-inflammatory effects against COVID-19 infection, cross-reactivity against tumor antigens, natural killer cell activation. COVID-19 proteins have oncolytic properties - HIV related B cell apoptosis and Coxsackievirus A21 oncolytic effects on myeloma and CD138+ plasma cells via intercellular adhesion molecule interaction. COVID-19’s effects plus the anti PD-1/PD-L1 antibodies immune response may be synergistic and merits further research.

Hepatic arterial infusion chemotherapy with or without lenvatinib for unresectable cholangiocarcinoma: a single-center retrospective study.

The purpose of this study is to compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin, fluorouracil and leucovorin (FOLFOX) plus lenvatinib and FOLFOX-HAIC alone in patients with unresectable cholangiocarcinoma. Retrospective analysis of patients receiving FOLFOX-HAIC with or without lenvatinib. Forty-one patients were included, with 22 patients receiving HAIC alone and 19 patients receiving HAIC plus lenvatinib. Combination treatment significantly prolonged overall survival and progression-free survival compared with HAIC alone. Grade 1-2 adverse events were more frequent in the combination group but manageable. No severe AEs or treatment-related deaths were reported. FOLFOX-HAIC plus lenvatinib has the potential to be a treatment option for unresectable cholangiocarcinoma.

Impact of endobiliary radiofrequency ablation on survival of patients with unresectable cholangiocarcinoma: a narrative review.

Cholangiocarcinoma (CCA) is a rare cancer originating from the biliary epithelium and accounts for about 3% of all gastrointestinal malignancies. Unfortunately, the majority of patients are not eligible for surgical resection at the time of diagnosis, because of the locally advanced stage or metastatic disease. The overall survival time of unresectable CCA is generally less than 1 year, despite current chemotherapy regimens. Biliary drainage is often required as a palliative treatment for patients with unresectable CCA. Recurrent jaundice and cholangitis tend to occur because of reobstruction of the biliary stents. This not only jeopardizes the efficacy of chemotherapy, but also causes significant morbidity and mortality. Effective control of tumor growth is crucial for prolonging stent patency and consequently patient survival. Recently, endobiliary radiofrequency ablation (ERFA) has been experimented as a treatment modality to reduce tumor mass, and delay tumor growth, extending stent patency. Ablation is accomplished by means of high-frequency alternating current which is released from the active electrode of an endobiliary probe placed in a biliary stricture. It has been shown that tumor necrosis releases intracellular particles which are highly immunogenic and activate antigen-presenting cells, enhancing local immunity directed against the tumor. This immunogenic response could potentially enhance tumor suppression and be responsible for improved survival of patients with unresectable CCA who undergo ERFA. Several studies have demonstrated that ERFA is associated with an increased median survival of approximately 6 months in patients with unresectable CCA. Furthermore, recent data support the hypothesis that ERFA could ameliorate the efficacy of chemotherapy administered to patients with unresectable CCA, without increasing the risk of complications. This narrative review discusses the results of the studies published in recent years and focuses on the impact that ERFA could have on overall survival of patients with unresectable cholangiocarcinoma.

Immune checkpoint inhibitors in cholangiocarcinoma.

Cholangiocarcinoma is an epithelial malignancy originating in the biliary tracts and frequently recurs even with surgical resection. Unresectable disease has a 5-year overall survival of less than 10%. Given this poor prognosis, additional therapies are urgently needed. Chemotherapy has been the mainstay of treatment for many years. However, with the incorporation of immunotherapy into the treatment of other malignancies, there has been a great deal of interest in immunotherapy for biliary cancers. Recently, durvalumab was approved in combination with gemcitabine and cisplatin for the treatment of unresectable cholangiocarcinoma in the first-line setting. However, predicting which patients may respond to immunotherapy remains a challenge due to the lack of a reliable biomarker.

Abstract CT153: Pemigatinib in Chinese patients with advanced/metastatic or surgically unresectable cholangiocarcinoma Including FGFR2 fusion or rearrangement: Updated overall survival from an open-label, single-arm, multicenter Phase II study

Abstract Background: Pemigatinib is a selective FGFR inhibitor that showed effectiveness and tolerability in patients with cholangiocarcinoma (CAA) with FGFR2 fusion or rearrangement. Data from prior data cutoffs (primary: Jan 29th, 2021; initial update: Dec 20th, 2021) showed that patients receiving pemigatinib had durable responses. Confirmed objective response rate (ORR) (60%) met the primary endpoint, median duration of response (DOR) was 8.3 months, median progression-free survival (PFS) was 9.1 months at the initial update (G-M. Shi et al. ASCO 2022). Safety results were also consistent with previously reported data on pemigatinib. Here we report updated overall survival (OS) results. Methods: Patients aged 18 years or older with recurrent or metastatic CCA that failed at least one prior systemic therapy were enrolled. Thirty-one subjects with documented FGFR2 fusion or rearrangement received 13.5 mg pemigatinib. The primary efficacy endpoint was ORR assessed by the independent radiological review committee (IRRC) per RECIST V1.1. And the second endpoints included disease control rate (DCR), DOR, PFS, and OS. Updated OS were evaluated by Cox proportional hazards model and summarized using Kaplan-Meier methods. Results: At data cutoff (December 28th, 2022), a total of 30 patients were assessed (1 participant excluded due to inadequate FGFR2 aberrant frequency). Median age was 56 years (range, 28-68).With a median OS follow-up of 25.6 months (95% CI, 23.0-25.8), the median OS was 23.9 months (95% CI, 15.2-NC), with 16 (53.3%) OS events. Estimated OS rate at 12 month, 18 month and 24 month were 73.3% (95% CI, 53.7%-85.7%), 66.5% (95% CI, 46.7%-80.4%), and 41.4% (95% CI, 22.4%-59.4%), respectively. No new safety signals were observed. Conclusions: These updated results demonstrated encouraging and durable survival benefit of pemigatinib in Chinese patients with recurrent or metastatic cholangiocarcinoma with FGFR2 fusion or rearrangement. Clinical trial identification: NCT04256980. Editorial acknowledgment: Guoming Shi and Xiaoyong Huang contributed equally to this work. Jian Zhou is the corresponding author. Citation Format: Guoming Shi, Xiaoyong Huang, Tianfu Wen, Tianqiang Song, Ming Kuang, Haibo Mou, Lequn Bao, Haitao Zhao, Hong Zhao, Xielin Feng, Bixiang Zhang, Tao Peng, Yubao Zhang, Xiangcheng Li, Hongsheng Yu, Yu Cao, Yang Luo, Ye Chen, Mingxia Chen, Jia Fan, Jian Zhou. Pemigatinib in Chinese patients with advanced/metastatic or surgically unresectable cholangiocarcinoma Including FGFR2 fusion or rearrangement: Updated overall survival from an open-label, single-arm, multicenter Phase II study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT153.

Endoscopic biliary treatment of unresectable cholangiocarcinoma: A meta-analysis of survival outcomes and systematic review.

Endoscopic radiofrequency ablation (ERFA), percutaneous radiofrequency ablation (PRFA), and photodynamic therapy (PDT), when used in conjunction with conventional biliary stenting, have demonstrated a survival benefit in patients with unresectable cholangiocarcinoma. To compare pooled survival outcomes, adverse event rates, and mean stent patency for those undergoing these procedures. A comprehensive literature review of published studies and abstracts from January 2011 to December 2020 was performed comparing survival outcomes in patients undergoing ERFA with stenting, biliary stenting alone, PRFA with stenting, and PDT with stenting for unresectable cholangiocarcinoma (CCA). Data from four studies demonstrated a pooled mean survival favoring ERFA as compared to biliary stenting alone (12.0 ± 0.9 mo vs 6.8 ± 0.3 mo, P < 0.001) as well as statistically improved median survival time (13 mo vs 8 mo, P < 0.001). Both ERFA with stenting and PRFA with stenting groups demonstrated statistical superiority to biliary stenting alone (P < 0.001 and P = 0.004, respectively). However, when comparing ERFA to PRFA, pooled data demonstrated overall higher mean survival in the ERFA with stenting cohort as compared to PRFA with stent cohort (12.0 + 0.9 mo vs 8.1 + 2.1 mo, P < 0.0001). Data from two studies demonstrated a pooled median survival favoring ERFA with stenting as compared to PDT with stenting (11.3 mo vs 8.5 mo, P = 0.02). While further prospective, randomized studies are needed to assess efficacy of ERFA, our meta-analysis demonstrated that this technique offers endoscopists a reasonable palliative method by which to treat patients with unresectable CCA that results in longer survival as compared to biliary stenting alone, percutaneous radiofrequency ablation with biliary stenting, and PDT with biliary stenting as well as an acceptable adverse event profile based on available published data.

Expert consensus on technical specifications for the clinical application of photodynamic therapy for cholangiocarcinoma

Photodynamic therapy(PDT) is an effective,minimally invasive method for tumor treatment. It can be applied for treating cholangiocarcinoma in combination with the implementation of biliary stent/external biliary drainage,or with systemic treatments including chemotherapy. Moreover,it is a primary application in the treatment of unresectable cholangiocarcinoma as well as an adjuvant treatment of residual postoperatively or locally recurrent tumors. It can control local tumor progression effectively,relieve biliary obstruction,improve life quality,and prolong survival,with the advantages of minimally invasive,precise and repeatable. To date,clinical evidence-based medicine for applying PDT to treat cholangiocarcinoma was limited,and there has been a lack of clinical specifications and consensus regarding the technique. Based on this,Group of Operative Surgery,Branch of Surgery,Chinese Medical Association,Group of Biliary Surgery,Branch of Surgery,Chinese Medical Association and Chinese Committee of Biliary Surgeons organized experts to discuss the indications,contraindications,technical protocol,efficacy evaluation,and management of complications when using PDT to treat cholangiocarcinoma. The consensus aims to provide a reference for promoting the clinical application of PDT in the treatment of cholangiocarcinoma.

Development and validation of a nomogram to predict cancer-specific survival with unresected cholangiocarcinoma undergoing external radiotherapy.

To analyze the prognostic factors of patients with cholangiocarcinoma (CCA) who were unresected and received radiotherapy to establish a nomogram model for the prediction of patient cancer-specific survival (CSS). Suitable patient cases were selected from the Surveillance, Epidemiology, and End Results (SEER) database, survival rates were calculated using the Kaplan-Meier method, prognostic factors were analyzed by Lasso, Cox regression, and nomogram was developed based on independent prognostic factors to predict 6 and 12 months CSS. The consistency index (C-index), calibration curve, and decision curve analysis (DCA) were tested for the predictive efficacy of the model, respectively. The primary site, tumor size, T-stage, M-stage, and chemotherapy (P < 0.05) were identified as independent risk factors after Cox and Lasso regression analysis. Patients in training cohort had a 6 months CSS rates was 68.6 ± 2.6%, a 12-month CSS rates was 49.0 ± 2.8%. The median CSS time of 12.00 months (95% CI: 10.17-13.83 months). The C-index was 0.664 ± 0.039 for the training cohort and 0.645 ± 0.042 for the validation cohort. The nomogram predicted CSS and demonstrated satisfactory and consistent predictive performance in 6 (73.4 vs. 64.9%) and 12 months (72.2 vs. 64.9%), respectively. The external validation calibration plot is shown AUC for 6- and 12-month compared with AJCC stage was (71.2 vs. 63.0%) and (65.9 vs. 59.8%). Meanwhile, the calibration plot of the nomogram for the probability of CSS at 6 and 12 months indicates that the actual and nomogram predict that the CSS remains largely consistent. DCA showed that using a nomogram to predict CSS results in better clinical decisions compared to the AJCC staging system. A nomogram model based on clinical prognostic characteristics can be used to provide CSS prediction reference for patients with CCA who have not undergone surgery but have received radiotherapy.

Hemoglobin and Neutrophil Count as Prognostic Factors in Cholangiocarcinoma Patients in 2nd Line Treatment Setting: Results from a Small Monocentric Retrospective Study.

Unresectable cholangiocarcinoma prognosis can be extremely variable due to different symptoms and sites of disease involvement at diagnosis and unpredictable chemotherapy response rates. Most patients will usually receive 1st line palliative chemotherapy with platinum compounds and Gemcitabine or Gemcitabine alone. Only a few patients maintain adequate performance status after first-line treatment failure: second-line treatment with FOLFOX or FOLFIRI chemotherapy has been used in this setting with modest overall survival improvement. There is a lack of data concerning whether laboratory findings might help clinicians in identifying those patients with the highest likelihood of benefiting from 2nd line treatment. The aim of this analysis is to assess the prognostic role of a series of easily available laboratory tests in patients with bile duct cancer who received 2nd line chemotherapy. Patients with unresectable bile duct cancer treated in 2nd-line setting with platinum-based chemotherapy doublet or FOLFIRI were enrolled. The primary objective of the analysis was to assess overall survival (OS) differences among patients based on the results of lab tests. Serum hemoglobin, neutrophil, lymphocyte, monocyte, platelet absolute count, creatinine, total bilirubin, albumin, LDH, circulating CEA and CA19.9 values were collected at the start of 2nd line treatment. Cut-off values for all lab tests were set by ROC curve analysis. Survival was calculated by the Kaplan-Meier method and differences in survival among stratification factors were assessed by Log-rank test. Cox-proportional-hazard regression was used for multivariate analysis. Level of statistical significance p was set at 0.05 for all tests. Correction for false discovery error rate was performed by Holm's stepdown procedure. A total of 46 patients were eligible. Median overall survival of the entire cohort was 8.98 months (95%CI: 6.68-13.93) while mean OS was 17.10 months (standard error: 3.16). Using 6.2 months OS landmark as classification variable for ROC curve analysis, only serum hemoglobin (cut-off: &gt;10 g/dL), albumin (cut-off: &gt;3.5 mg/dL), CA19.9 (cut-off: ≤668 UI/mL), monocyte (cut-off: ≤510/mmc) and neutrophil count (cut-off: ≤5140/mmc) were significantly associated with the chosen end-point. Multivariate analysis confirmed an independent statistically significant impact on overall survival only for hemoglobin (Exp(b): 0.12, p = 0.0023) and neutrophil count (Exp(b): 0.30, p = 0.0039). Based on these results, using both hemoglobin and neutrophil count, three prognostic groups were defined: patients with both favorable factors had 12.63 months median OS vs. 6.75 months of patients with only one favorable factor vs. 1.31 months of those with neither. The difference between these three groups of patients was statistically significant (p &lt; 0.0001). Second-line palliative chemotherapy can be a potentially useful option for a few patients with unresectable/metastatic bile duct cancer. Even though assessment of patients' prognosis might be difficult due to the complex behavior of this disease, a series of easily available laboratory tests might be used for these means: serum hemoglobin and neutrophil count we0re able to define subsets of patients with entirely different prognoses. It is hoped that this score will be prospectively validated in a larger group of patients in order to improve treatment decisions in patients with unresectable bile duct cancer candidate to receive palliative 2nd line chemotherapy.

New perspectives in unresectable cholangiocarcinoma? Evaluation of chemosaturation with percutaneous hepatic perfusion as a palliative treatment option

Cholangiocarcinoma (CCA) are the second most common primary liver tumors and carry a dismal prognosis. Chemosaturation with percutaneous hepatic perfusion (PHP) is a palliative, intra-arterial therapeutic approach that provides a high dose chemotherapy of the liver with reduced systemic exposure. Aim of this retrospective, monocentric study was to analyze PHP as a palliative treatment for unresectable CCA. Toxicity, adverse events and complications were classified using the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Overall response rate (ORR) and disease control rate (DCR) were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST1.1). Median overall survival (mOS), median progression-free survival (mPFS) and hepatic mPFS (mhPFS) were computed using Kaplan–Meier estimation. In total 17 patients were treated with 42 PHP between 10/2014 and 09/2020. No significant complications occurred during the interventions. mOS was 27.6 (interquartile range (IQR) 16.5–37) months from first diagnosis and 9.9 (IQR 3.8–21) months from first PHP. mPFS was 4 (IQR 2–7) and mhPFS was 4 (IQR 3–10) months. ORR was 25% and DCR 75%. Significant, but transient hematotoxicity was frequent with grade 3/4 thrombopenia after 50%, leukopenia after 26% and anaemia after 21% of the interventions. An increase of transaminases (AST increase after 21% and ALT increase after 14% of the PHP) developed more often than a deterioration of the liver synthesis capacity. Salvage treatment with PHP has the potential to prolong life in selected patients with unresectable, refractory cholangiocarcinoma. The interventional procedure is safe. Post-interventional toxicity is frequent but manageable.

The multidisciplinary management of cholangiocarcinoma.

Cholangiocarcinoma is a lethal malignancy of the biliary epithelium that can arise anywhere along the biliary tract. Surgical resection confers the greatest likelihood of long-term survivability. However, its insidious onset, difficult diagnostics, and resultant advanced presentation render the majority of patients unresectable, highlighting the importance of early detection with novel biomarkers. Developing liver-directed therapies and emerging targeted therapeutics may offer improved survivability for patients with unresectable or advanced disease. In this article, the authors review the current multidisciplinary standards of care in resectable and unresectable cholangiocarcinoma, with an emphasis on novel biomarkers for early detection and nonsurgical locoregional therapy options.

Efficacy and Safety of External-beam Radiation Therapy for Unresectable Primary or Local Recurrent Cholangiocarcinoma.

Treatment options for unresectable cholangiocarcinoma are limited. The aim of the study was to evaluate the clinical outcomes of definitive external-beam radiation therapy (EBRT) for patients with unresectable cholangiocarcinoma. Patients with unresectable primary cholangiocarcinoma, or local recurrent cholangiocarcinoma after primary surgery, without distant metastasis who received definitive EBRT (≥45 Gy) between January 2006 and December 2020 at our Institution were analyzed retrospectively. EBRT was basically performed using conventional fractionation (1.8-2 Gy per fraction). Prophylactic nodal irradiation was not performed. A total of 21 consecutive patients were analyzed: 7 primary and 14 recurrent cases. The median age was 70 (range=38-85) years at initiation of EBRT. A median dose of 54 (range=45-60) Gy comprising 1.8 (range=1.8-3) Gy per fraction was administered to the primary/recurrent local tumor site. The median follow-up period was 21.6 months. The 2-year overall survival, cause-specific survival, progression-free survival, and local recurrence-free rates were 35.7, 35.7, 16.1, and 32.7%, respectively. Long-term local control (>2 years after EBRT) was achieved in 19.0%. Grade 3 toxicities related to EBRT were observed in 4.8% (duodenum hemorrhage). No grade 4 or higher toxicities were observed. Definitive EBRT for unresectable cholangiocarcinoma was feasible and achieved long-term local control in a subset of patients. As the avoidance of local recurrence may lead to the benefits of prolonging biliary patency and subsequently alleviating the need for an invasive procedure for biliary drainage, EBRT could be one sustainable therapeutic option for patients with unresectable cholangiocarcinoma.