Unresectable Intrahepatic Cholangiocarcinoma Research Articles

Chemotherapy combined with lenvatinib and PD-1 may be a potential better alternative option for advanced unresectable intrahepatic cholangiocarcinoma: a retrospective real-world study.

Currently, the prognosis of advanced intrahepatic cholangiocarcinoma (ICC) is poor, and the current treatment methods are not effective. The aim of this study was to evaluate the anticancer efficacy of chemotherapy combined with PD-1 inhibitors and tyrosine kinase inhibitors (TKIs) in patients with ICC. We retrospectively screened patients with advanced intrahepatic cholangiocarcinoma (ICC) who received chemotherapy combined with lenvatinib and PD-1. We evaluated overall survival (OS), progression-free survival (PFS), the objective response rate (ORR), the disease control rate (DCR), the tumor shrinkage rate, and safety. We enrolled 95 patients with ICC and divided them into three groups with a median follow-up duration of 15.1 months. The chemotherapy group (chemo-regimen group), chemotherapy combined with immune checkpoint inhibitors (dual-regimen group), and chemotherapy combined with lenvatinib (triple-regimen group) had median OS times of 13.1 months, 20.8 months, and 39.6 months, respectively. Notably, the triple-regimen group had a significantly longer OS than did the chemo-regimen and dual-regimen groups. The chemo-regimen group, dual-regimen group, and triple-regimen group reported median PFS durations of 4.8 months, 11.9 months, and 23.4 months, respectively. Both combination groups exhibited significantly longer PFS than the chemotherapy-only group (P<0.05). The ORRs of the chemo-regimen, dual-regimen, and triple-regimen groups were 18.2%, 55.5%, and 54.7%, respectively. The DCRs were 72.7%, 90%, and 96.2%, respectively, indicating significantly better outcomes in the combination therapy groups. The combination of chemotherapy with PD-1 inhibitors and lenvatinib demonstrates considerable efficacy and tolerability as a treatment strategy for patients with advanced ICC.

971P Chemotherapy combined with lenvatinib and PD-1 may be a potential better alternative optionfor advanced unresectable intrahepatic cholangiocarcinoma: A retrospective real-world study

971P Chemotherapy combined with lenvatinib and PD-1 may be a potential better alternative optionfor advanced unresectable intrahepatic cholangiocarcinoma: A retrospective real-world study

Clinical Effectiveness of Drug-Eluting Microsphere Transcatheter Arterial Chemoembolization Combined with First-Line Chemotherapy as the Initial Treatment for Patients with Unresectable Intrahepatic Cholangiocarcinoma

PurposeTo evaluate the safety and effectiveness of the combination of drug-eluting microsphere (DEM) transcatheter arterial chemoembolization (TACE) with those of chemotherapy in treating unresectable intrahepatic cholangiocarcinoma (ICC). Materials and MethodsSeventy patients diagnosed with unresectable ICC between January 2016 and December 2020 were retrospectively included in this study. Of these, 39 patients received DEM-TACE and first-line chemotherapy (TACE+Chemo group) and 31 received chemotherapy alone (Chemo group). Propensity score matching was performed to reduce selection bias between the TACE+Chemo and the Chemo groups. Differences in tumor response, progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were compared between 2 two groups. ResultsThe patients in the TACE+Chemo group had better median OS (18.6 vs 11.9 months; P = .018), median PFS (11.9 vs 6.9 months, P = .033), and objective response rates (56.8% vs 13.3%; P < .001) than those in the Chemo group. TRAEs showed a higher incidence of transient elevation of transaminase and abdominal pain in the TACE+Chemo group than in the Chemo group (P < .001). ConclusionsCompared with chemotherapy alone, DEM-TACE combined with first-line chemotherapy may be a viable and safe treatment option for unresectable ICC.

Preliminary clinical use of hepatic arterial infusion chemotherapy combined with lenvatinib and tislelizumab in the treatment of unresectable intrahepatic cholangiocarcinoma

Objective: To evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and tislelizumab in the treatment of unresectable intrahepatic cholangiocarcinoma (ICC). Methods: The clinical data of 12 patients with unresectable ICC who received HAIC combined with lenvatinib and tislelizumab in the First Affliated Hospital of Soochow University from October 2021 to April 2023 were retrospectively analyzed. HAIC included gemcitabine plus oxaliplatin; this regimen was combined with lenvatinib and tislelizumab within 3-7 days after its initial administration. Relevant laboratory examinations were performed before each cycle of HAIC, and enhanced computed tomography/magnetic resonance imaging examinations were performed every 6-9 weeks. Tumor response to treatment was evaluated using the modified Response Evaluation Criteria in Solid Tumors. The objective response rate, disease control rate, progression-free survival, overall survival, and treatment-related adverse reactions of patients with ICC were statistically analyzed. Results: The objective response rate to HAIC combined with lenvatinib and tislelizumab was 6/12; the disease control rate was 8/12; the median progression-free survival was 11.8 months; and the median overall survival was 14.2 months. Three patients had grade Ⅳ adverse reactions (increased alanine aminotransferase and aspartate aminotransferase thrombocytopenia), while three patients had grade Ⅲ adverse reactions (increased total bilirubin, alanine aminotransferase, and aspartate aminotransferase). The remaining patients had grade Ⅰ-Ⅱ adverse reactions. There were no serious complications related to interventional surgery. Conclusions: Use of HAIC (gemcitabine plus oxaliplatin) combined with lenvatinib and tislelizumab in the treatment of unresectable ICC may be safe and feasible. Preliminary clinical studies have shown that this combination can improve the survival and prognosis of patients with ICC.

Successful intrahepatic cholangiocarcinoma conversion surgery after administration of fibroblast growth factor receptor inhibitor.

We describe a case of a 47-year-old male patient with initially unresectable intrahepatic cholangiocarcinoma of the right liver lobe with tumor thrombi extending from the right bile duct to the common and left bile ducts. Conventional chemotherapy with gemcitabine and cisplatin for 19months resulted in progressive disease. Subsequently, a comprehensive genome profile revealed fibroblast growth factor receptor 2 rearrangement, and hence, pemigatinib administration was initiated. After 6months of pemigatinib therapy, significant shrinking of the tumor and disappearance of the tumor thrombi in the common and left bile duct were observed. Subsequently, the patient underwent conversion surgery, resulting in successful radical resection of the tumor. The patient has been disease-free for 7months.

Hepatic arterial infusion chemotherapy: a review with technical notes

Combined hepatic artery infusion (HAI) and systemic chemotherapy have demonstrated its clinical efficacy in prolonging overall survival in unresectable intrahepatic cholangiocarcinoma and as a conversion to treatment strategy in a small proportion of patients. The utilization of HAI chemotherapy is restricted by the scarcity of surgeons and oncologists who are well-experienced in its use. This represents a significant drawback of this treatment method. In recent years, a solid push to expand its use, mainly in the United States and recently also in Europe, has been made possible by the HAI Consortium Research Network. Results of ongoing Clinical Trials are eagerly awaited to give the basis for further expansion of this technique and oncological treatment outside of historically established centers. In this technical note review, we aim to give a brief historical description of the origins and evolution of intra-arterial chemotherapy for unresectable intrahepatic cholangiocarcinoma. We will, therefore, discuss the surgical technique by providing some tips and tricks without neglecting the difficulties that may be encountered.

Hepatic artery infusion pump (HAIP) therapy in combination with targeted delivery of IL-12 for patients with metastatic colorectal cancer or intrahepatic cholangiocarcinoma: a phase II trial protocol.

Treatment of advanced liver tumors remains challenging. Although immune checkpoint inhibition has revolutionized treatment for many cancers, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. Investigation into additional immunomodulatory therapies for these cancers is needed. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with robust anti-tumor activity, but systemic adverse effects largely terminated therapeutic development of recombinant human IL-12 (rhIL-12). PDS01ADC is a novel human monoclonal antibody (NHS76) conjugated to two IL-12 heterodimers with established safety in phase I trials. The NHS76 antibody specifically targets histone/DNA complexes which are accessible only in regions of cell death and this antibody has been shown to accumulate locally in tumors. Patients with unresectable metastatic colorectal cancer (mCRC) or unresectable intrahepatic cholangiocarcinoma (ICC) will receive synchronization of subcutaneous PDS01ADC with floxuridine delivered via a hepatic artery infusion pump (HAIP). The primary outcome measured in this study will be overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes measured in this study will include hepatic and non-hepatic progression-free survival (PFS), overall survival, and safety of PDS01ADC combination therapy with HAIP. Poor clinical response of these liver tumors to immunotherapy is likely due to various factors, including poor immune infiltrate into the tumor and immunosuppression by the tumor microenvironment. By exploiting the tumor cell death induced by HAIP locoregional therapy in combination with systemic chemotherapy, PDS01ADC is poised to modulate the tumor immune microenvironment to improve outcomes for patients undergoing HAIP therapy. ClinicalTrials.gov (ID NCT05286814 version 2023-10-18); https://clinicaltrials.gov/study/NCT05286814?term=NCT05286814&rank=1.

First-line hepatic arterial infusion chemotherapy plus lenvatinib and PD-(L)1 inhibitors versus systemic chemotherapy alone or with PD-(L)1 inhibitors in unresectable intrahepatic cholangiocarcinoma

PurposeLimited treatment options exist for unresectable intrahepatic cholangiocarcinoma (ICC), with systemic chemotherapy (SC) serving as the primary approach. This study aimed to assess the effectiveness of first-line hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib and PD-(L)1 inhibitors (HLP) compared to SC combined with PD-(L)1 inhibitors (SCP) or SC alone in treating unresectable ICC.MethodsPatient with unresectable ICC who underwent first-line treatment with HLP, SCP or SC from January 2016 to December 2022 were retrospectively analyzed. The study evaluated and compared efficacy and safety outcomes across the three treatment groups.ResultsThe study comprised 42, 49, and 50 patients in the HLP, SCP, and SC groups, respectively. Median progression-free survival (PFS) times were 30.0, 10.2, and 6.5 months for HLP, SCP, and SC groups. While the SC group had a median overall survival (OS) time of 21.8 months, the HLP and SCP groups hadn’t reached median OS. The HLP group demonstrated significantly superior PFS (p < 0.001) and OS (p = 0.014) compared to the others. Moreover, the HLP group exhibited the highest objective response rate (ORR) at 50.0% and the highest disease control rate (DCR) at 88.1%, surpassing the SC group (ORR, 6.0%; DCR, 52.0%) and SCP group (ORR, 18.4%; DCR, 73.5%) (p < 0.05). Generally, the HLP group reported fewer grades 3–4 adverse events (AEs) compared with others.ConclusionIn contrast to systemic chemotherapy with or without PD-(L)1 inhibitors, the triple combination therapy incorporating HAIC, lenvatinib, and PD-(L)1 inhibitors showcased favorable survival benefits and manageable adverse events for unresectable ICC.

Efficacy and safety of lenvatinib plus durvalumab combined with hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma.

e16184 Background: The prognosis for unresectable intrahepatic cholangiocarcinoma (ICC) is poor and the efficacy of traditional chemotherapy remains unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) is effective in patients with unresectable ICC. In this study, we determined the preliminary clinical efficacy and safety of lenvatinib plus durvalumab combined with FOLFOX-HAIC in patients with untreated, unresectable ICC. Methods: Between July 2021 and July 2023, patients with unresectable ICC who initially received lenvatinib plus durvalumab combined with FOLFOX-HAIC at the Sun Yat-Sen University Cancer Center (SYSUCC) were retrospectively reviewed for eligibility. Efficacy was evaluated by tumor response rate and survival, and safety was assessed by the frequency of key adverse events (AEs). Results: A total of 28 eligible patients were enrolled. The objective response rates (ORRs) based on mRECIST and RECIST 1.1 criteria were 65.2% and 39.1%, respectively. The median OS was 17.9 months (95% CI, 5.7–30.1) and the median PFS was 11.9 months (95% CI, 6.7–17.1). Most patients (92.9%) experienced adverse events (AEs), whereas 46.5% (13/28) experienced grade 3 or 4 AEs. Conclusions: Lenvatinib plus durvalumab combined with FOLFOX-HAIC showed promising antitumor activity and manageable AEs in patients with treatment-naive unresectable ICC. This regimen may be suitable as a novel first-line treatment option for this patient population.

Comparison of efficacy and safety of conventional transarterial chemoembolization and drug-eluting bead transarterial chemoembolization in unresectable intrahepatic cholangiocarcinoma: A multicenter retrospective cohort study

PurposeThe efficacy and safety of drug-eluting bead transarterial chemoembolization (DEB-TACE) and conventional TACE (c-TACE) in the treatment of patients with unresectable intrahepatic cholangiocarcinoma (ICC) remained controversial. Therefore, we aimed to compare the efficacy and safety between c-TACE and DEB-TACE among patients with ICC. MethodBetween June 10, 2016 and November 19, 2022, consecutive patients with pathological diagnoses of ICC were divided into the DEB-TACE group and the c-TACE group based on the type of TACE treatment they received. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS) between the two groups. Propensity score matching (PSM) was used to balance the characteristics between the c-TACE group and the DEB-TACE group. ResultsA total of 132 patients were included in this study, with 64 patients in the c-TACE group and 68 patients in the DEB-TACE group. The median OS for c-TACE and DEB-TACE was 5 and 12 months, respectively. The objective response rate (ORR) for c-TACE and DEB-TACE was 0 % and 66.2 %, respectively; the disease control rate (DCR) was 37.5 % and 91.2 %. There were no significant differences between c-TACE and DEB-TACE among adverse effects at 3 months after treatment (P > 0.05). The results remained consistent after PSM. The Cox regression demonstrated that the DEB-TACE was an independent protective factor for OS. ConclusionsPatients in the DEB-TACE group had longer OS and higher ORR and DCR than those in the c-TACE group, but no significant difference was observed between the two groups regarding adverse effects.

Efficacy and safety of arterial FOLFOX chemotherapy plus anti-PD-(L)1 immunotherapy as first-line treatment for unresectable intrahepatic cholangiocarcinoma: A propensity score matched analysis.

e16189 Background: This study aimed to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) plus anti-programmed death (ligand)-1 [PD-(L)1] immunotherapy compared to systemic chemotherapy (SCT) plus anti-PD-(L)1 immunotherapy as first-line treatment for patients with unresectable intrahepatic cholangiocarcinoma (uICC). Methods: In this retrospective study, unresectable treatment-naive ICC patients who were treated with HAIC plus anti-PD-(L)1 immunotherapy [HAIC+αPD-(L)1] or SCT plus anti-PD-(L)1 immunotherapy [SCT+αPD-(L)1] were included. The clinical characteristics, therapeutic outcomes and adverse events (AEs) of patients between the two groups were compared. The propensity score matching (PSM) was performed to minimize biases between groups. Results: From January 2019 to January 2023, a total of 182 patients were enrolled, including 147 patients in HAIC+αPD-(L)1 group and 35 patients in SCT+αPD-(L)1 group. After PSM, 61 and 26 patients were included in the HAIC+αPD-(L)1 and SCT+αPD-(L)1 groups, respectively. The HAIC+αPD-(L)1 group showed longer median overall survival (OS) and progression free survival (PFS) than the SCT+αPD-(L)1 group (OS: 14.5 vs 10.5 months, P = 0.019; PFS: 6.4 vs 10.1 months, P = 0.020). The disease control rate of HAIC+αPD-(L)1 group were higher than those of SCT+αPD-(L)1 group (91.8% vs 69.2%, P = 0.007). The overall incidence of adverse events (AEs) was comparable between the two groups, but the HAIC+αPD-(L)1 group showed a lower incidence of grade 3~4 AEs related to anemia, weight loss and fatigue. Conclusions: HAIC plus anti-PD-(L)1 immunotherapy had acceptable toxic effects and might improve outcomes compared to SCT plus anti-PD-(L)1 immunotherapy as first-line treatment for patients with uICC.

Hypofractionated Radiotherapy-Related Lymphopenia Is Associated With Worse Survival in Unresectable Intrahepatic Cholangiocarcinoma.

The aim of this study was to evaluate the incidence of radiotherapy (RT)-related lymphopenia, its predictors, and association with survival in unresectable intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated-RT (HF-RT). Retrospective analysis of 96 patients with unresectable ICC who underwent HF-RT (median 58.05 Gy in 15 fractions) between 2009 and 2022 was performed. Absolute lymphocyte count (ALC) nadir within 12 weeks of RT was analyzed. Primary variable of interest was severe lymphopenia, defined as Grade 3+ (ALC <0.5 k/μL) per CTCAE v5.0. Primary outcome of interest was overall survival (OS) from RT. Median follow-up was 16 months. Fifty-two percent of patients had chemotherapy pre-RT, 23% during RT, and 40% post-RT. Pre-RT, median ALC was 1.1 k/μL and 5% had severe lymphopenia. Post-RT, 68% developed RT-related severe lymphopenia. Patients who developed severe lymphopenia had a significantly lower pre-RT ALC (median 1.1 vs. 1.5k/μL, P =0.01) and larger target tumor volume (median 125 vs. 62 cm 3 , P =0.02). In our multivariable Cox model, severe lymphopenia was associated with a 1.7-fold increased risk of death ( P =0.04); 1-year OS rates were 63% vs 77% ( P =0.03). Receipt of photon versus proton-based RT (OR=3.50, P =0.02), higher mean liver dose (OR=1.19, P <0.01), and longer RT duration (OR=1.49, P =0.02) predicted severe lymphopenia. HF-RT-related lymphopenia is an independent prognostic factor for survival in patients with unresectable ICC. Patients with lower baseline ALC and larger tumor volume may be at increased risk, and use of proton therapy, minimizing mean liver dose, and avoiding treatment breaks may reduce RT-related lymphopenia.

Efficacy and safety of lenvatinib plus durvalumab combined with hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma.

The prognosis for unresectable intrahepatic cholangiocarcinoma (ICC) is poor and the efficacy of traditional chemotherapy remains unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) is effective in patients with unresectable ICC. In this study, we determined the preliminary clinical efficacy and safety of lenvatinib plus durvalumab combined with FOLFOX-HAIC in patients with untreated, unresectable ICC. Between July 2021 and July 2023, patients with unresectable ICC who initially received lenvatinib plus durvalumab combined with FOLFOX-HAIC at the Sun Yat-Sen University Cancer Center (SYSUCC) were reviewed for eligibility. Efficacy was evaluated by tumor response rate and survival, and safety was assessed by the frequency of key adverse events (AEs). A total of 28 eligible patients were enrolled. The objective response rates (ORRs) based on mRECIST and RECIST 1.1 criteria were 65.2% and 39.1%, respectively. The median OS was 17.9 months (95% CI, 5.7-30.1) and the median PFS was 11.9 months (95% CI, 6.7-17.1). Most patients (92.9%) experienced adverse events (AEs), whereas 46.5% (13/28) experienced grade 3 or 4 AEs. Lenvatinib plus durvalumab combined with FOLFOX-HAIC showed promising antitumor activity and manageable AEs in patients with treatment-naive unresectable ICC. This regimen may be suitable as a novel first-line treatment option for this patient population.

Anti-PD-1 antibody in combination with radiotherapy as first-line therapy for unresectable intrahepatic cholangiocarcinoma

BackgroundUnresectable intrahepatic cholangiocarcinoma (iCCA) has a poor prognosis despite treatment with standard combination chemotherapy. We aimed to evaluate the efficacy and safety of radiotherapy in combination with an anti-PD-1 antibody in unresectable iCCA without distant metastases.MethodsIn this phase II study, patients with histopathologically confirmed unresectable primary or postoperative recurrent iCCA without distant metastases were enrolled. Patients received external radiotherapy with a dose of ≥45 Gy (2-2.5 Gy per fraction), followed by anti-PD-1 immunotherapy (camrelizumab 200 mg once, every 3 weeks) initiated within 7 days after completion of radiotherapy as first-line therapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The secondary end points included safety, objective response rate (ORR), disease control rate (DCR), and overall survival (OS).ResultsFrom December 2019 to March 2021, 36 patients completed radiotherapy and at least one cycle of immunotherapy and were included in efficacy and safety analyses. The median follow-up was 19.0 months (IQR 12.0-24.0), and the one-year PFS rate was 44.4% (95% CI, 30.8-64.0). The median PFS was 12.0 months (95% CI, 7.5-not estimable); the median OS was 22.0 months (95% CI, 15.0-not estimable). The ORR was 61.1% and the DCR was 86.1%. Seventeen of 36 (47.2%) patients experienced treatment-related adverse effects (AEs) of any grade. The most common AE was reactive cutaneous capillary endothelial proliferation (25.0%). Five (13.9%) patients experienced grade ≥3 treatment-related AEs, including decreased lymphocyte (5.6%), bullous dermatitis (2.8%), decreased platelet count (2.8%), and deep-vein thrombosis (2.8%).ConclusionsExternal radiotherapy plus camrelizumab, as first-line therapy, met its primary endpoint and showed antitumor activity and low toxicity levels in patients with unresectable iCCA without distant metastases, warranting further investigation.Trial registrationNCT03898895. Registered 2 April 2019.

Analysis of the efficacy and safety of hepatic arterial infusion chemotherapy for unresectable hepatitis B-related intrahepatic cholangiocarcinoma

Objective: To explore the efficacy and safety of hepatic arterial infusion chemotherapy(HAIC) for unresectable hepatitis B-related intrahepatic cholangiocarcinoma(ICC). Methods: This is a retrospective controlled study. Data from 140 unresectable ICC patients who received HAIC treatment at Sun Yat-sen University Cancer Center from March 2015 to June 2023 were retrospectively collected, including 72 patients in the hepatitis B surface antigen(HBsAg)negative group (43 males and 29 females, aged (59.6±9.5)years(range: 34 to 81 years)), 68 cases in the HBsAg-positive group (48 males, 20 females, aged (53.4±11.4)years(range: 29 to 82 years)). HAIC treatment used the FOLFOX regimen combined with oxaliplatin, leucovorin,and fluorouracil. The differences in effects, prognosis,and adverse reactions between the two groups of patients after HAIC treatment were analyzed. All variables were expressed as categorical data. The χ2 test or Fisher's exact probability method was used to compare between groups. The Kaplan-Meier method was used to draw survival curves. The difference of survival curve between groups were compared through the Log-rank test. Results: According to the Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1,the objective response rate(ORR) of the HBsAg-negative group was 23.2%(16/69),and the ORR of the HBsAg-positive group was 40.3%(25/62). The difference in ORR between the two groups was statistically significant(χ2=4.459,P=0.035). According to the modified RECIST(mRECIST) criteria,the ORR of the HBsAg-negative group was 27.5%(19/69), and the ORR of the HBsAg-positive group was 45.2%(28/62). The difference in ORR between the two groups was statistically significant(χ2=4.410,P=0.036). The median progression-free survival(PFS) of the HBsAg-negative group and the positive group were 7.1 months(95%CI: 5.8 to 13.2 months) and 7.3 months (95%CI: 5.7 to 10.3 months), respectively, and the median overall survival(OS) were 16.3 months (95%CI: 12.5 to 33.9 months) and 15.9 months (95%CI: 9.2 to 20.7 months) respectively. There were no statistically significant differences in PFS and OS between the two groups (both P>0.05). The main serious adverse reactions of the two groups of patients included increased AST, increased ALT, thrombocytopenia,and neutropenia. There were no statistically significant differences in various adverse reactions between the two groups after HAIC treatment (all P>0.05). Conclusion: Patients with HBsAg-positive unresectable ICC are more likely to benefit from HAIC treatment.

Robotic Versus Open Hepatic Arterial Infusion Pump Placement for Unresectable Intrahepatic Cholangiocarcinoma.

Hepatic arterial infusion pump (HAIP) chemotherapy is an effective treatment for patients with unresectable intrahepatic cholangiocarcinoma (iCCA). HAIP chemotherapy requires a catheter inserted in the gastroduodenal artery and a subcutaneous pump. The catheter can be placed using an open or robotic approach. This study aimed to compare perioperative outcomes of robotic versus open HAIP placement in patients with unresectable iCCA. We analyzed patients with unresectable iCCA included in the PUMP-II trial from January 2020 to September 2022 undergoing robotic or open HAIP placement at Amsterdam UMC, Erasmus MC, and UMC Utrecht. The primary outcome was time to functional recovery (TTFR). In total, 22 robotic and 28 open HAIP placements were performed. The median TTFR was 2days after robotic placement versus 5 days after open HAIP placement (p<0.001). One patient (4.5%) in the robotic group underwent a conversion to open because of a large bulky tumor leaning on the hilum immobilizing the liver. Postoperative complications were similar-36% (8/22) after robotic placement versus 39% (11/28) after open placement (p=1.000). The median length of hospital stay was shorter in the robotic group-3 versus 5 days (p<0.001). All 22 robotic patients initiated HAIP chemotherapy post-surgery, i.e. 93% (26/28) in the open group (p=0.497). The median time to start HAIP chemotherapy was 14 versus 18 days (p=0.153). Robotic HAIP placement in patients with unresectable iCCA is a safe and effective procedure and is associated with a significantly shorter TTFR and hospital stay than open HAIP placement.

Contemporary trends and outcomes after liver transplantation and resection for intrahepatic cholangiocarcinoma

BackgroundLiver transplantation has been shown to be superior to resection in highly selected patients with perihilar cholangiocarcinoma, yet has traditionally been contraindicated for intrahepatic cholangiocarcinoma. Herein, we aimed to examine contemporary trends and outcomes for surgical resection and liver transplantation for intrahepatic cholangiocarcinoma. MethodsThe National Cancer Database was queried for patients presenting with stage I-III intrahepatic cholangiocarcinoma between 2010 and 2018 who underwent resection or liver transplantation. Overall survival was compared with Kaplan-Meier and multivariable Cox proportional hazards methods stratified by management. Secondary analysis of patients undergoing transplant for cholangiocarcinoma was performed with the United Network for Organ Sharing database. ResultsOf 2,565 patients, 2,412 (94.0%) underwent resection and 153 (5.96%) liver transplantation of which 84 (54.9%) received neoadjuvant therapy. Utilization of liver transplantation remained between 3.9-7.8% annually. Unadjusted 5-year overall survival was higher for liver transplantation than resection (59.8% vs 39.9%, p=0.0067). Yet, adjusted analysis revealed no significant difference in mortality (hazard ratio 0.91, 95% confidence interval 0.66-1.27, p=0.58). On secondary analysis including 437 patients with all subtypes of cholangiocarcinoma, unadjusted 5-year overall survival was higher for non-cholangiocarcinoma indications (79% vs 52-54%, p<0.001). ConclusionUtilization of liver transplantation for intrahepatic cholangiocarcinoma remains low and many cases are likely incidental. While partial hepatectomy remains the standard of care for patients with resectable disease, our findings suggest that highly selected patients with unresectable intrahepatic cholangiocarcinoma may achieve favorable outcomes after liver transplantation. Granular, prospective data is needed to identify patients most likely to benefit from transplant and allocate scarce liver grafts.

Factors Impacting Survival After Transarterial Radioembolization in Patients with Unresectable Intrahepatic Cholangiocarcinoma: A Combined Analysis of the Prospective CIRT Studies

PurposeTransarterial radioembolization (TARE) with Yttrium-90 resin microspheres is a treatment option for patients with intrahepatic cholangiocarcinoma (ICC). However, optimising the timing of TARE in relation to systemic therapies and patient selection remains challenging. We report here on the effectiveness, safety, and prognostic factors associated with TARE for ICC in a combined analysis of the prospective observational CIRT studies (NCT02305459 and NCT03256994).MethodsA combined analysis of 174 unresectable ICC patients enrolled between 2015 and 2020 was performed. Patient characteristics and treatment-related data were collected at baseline; adverse events and time-to-event data (overall survival [OS], progression-free survival [PFS] and hepatic PFS) were collected at every follow-up visit. Log-rank tests and a multivariable Cox proportional hazard model were used to identify prognostic factors.ResultsPatients receiving a first-line strategy of TARE in addition to any systemic treatment had a median OS and PFS of 32.5 months and 11.3 months. Patients selected for first-line TARE alone showed a median OS and PFS of 16.2 months and 7.4 months, whereas TARE as 2nd or further treatment-line resulted in a median OS and PFS of 12 and 9.3 months (p = 0.0028), and 5.1 and 3.5 months (p = 0.0012), respectively. Partition model dosimetry was an independent predictor for better OS (HR 0.59 [95% CI 0.37–0.94], p = 0.0259). No extrahepatic disease, no ascites, and < 6.1 months from diagnosis to treatment were independent predictors for longer PFS.ConclusionThis combined analysis indicates that in unresectable ICC, TARE in combination with any systemic treatment is a promising treatment option.Level of evidence: level 3, Prospective observationalGraphic

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]

Phase II study evaluating the efficacy of PDS0301 in combination with hepatic artery infusion pump (HAIP) and systemic therapy for patients with metastatic colorectal cancer or intrahepatic cholangiocarcinoma.

TPS586 Background: Treatment of advanced liver tumors continues to pose significant challenges. Despite advances in immunotherapies, including immune checkpoint blockade, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. The lack of robust clinical efficacy is likely myriad, including immunosuppression by the tumor microenvironment and poor susceptibility of these tumors to immune infiltration and surveillance. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with extensive anti-tumor properties, but therapeutic development of recombinant human IL-12 (rhIL-12) was halted due to significant systemic toxicities. PDS0301 (formerly M9241) is a novel human monoclonal antibody (NHS76) fused to two IL-12 heterodimers. The NHS76 antibody specifically targets histone/DNA complexes in regions of cellular necrosis resulting in accumulation within tumors. Importantly, recent Phase I trials have shown PDS0301 monotherapy to be well tolerated. We hypothesize that synchronization of PDS0301 administration with tumor cell death induced by locoregional and systemic chemotherapies will demonstrate increased efficacy over standard of care therapy. Methods: This is a single center, non-randomized Phase II study to determine the safety and efficacy of PDS0301 in combination with floxuridine (FUDR) administered by hepatic artery infusion pump (HAIP) and systemic chemotherapies in patients with either unresectable metastatic colorectal cancer (mCRC) or intrahepatic cholangiocarcinoma (ICC). Eligibility criteria include histologically or cytologically confirmed colorectal adenocarcinoma metastatic to the liver (Cohort 1) or unresectable intrahepatic cholangiocarcinoma with no evidence of extrahepatic metastases (Cohort 2). Patients will receive HAIP-administered (FUDR) plus PDS0301 at a starting dose of 12mcg/kg in 28-day cycles. Beginning in cycle 2, systemic chemotherapy with FOLFOX (Leucovorin, 5-Fluorouracil [5-FU], and Oxaliplatin) or FOLFIRI (Leucovorin, 5-FU and Irinotecan) for mCRC or GemOx (Gemcitabine and Oxaliplatin) for ICC will be introduced. Patients will be evaluated for response at eight-week intervals. The primary endpoint is overall response rates to PDS0301 and HAIP/systemic combination therapy. Secondary objectives include hepatic progression-free survival (PFS), extra-hepatic PFS, overall survival, and safety. Scientific objectives include determination of microenvironment alterations through pre-and post-treatment biopsies as well as evaluation of peripheral immune subsets and cytokines. To date, we have enrolled 8 of 23 patients in Cohort 1. Clinical trial information: NCT05286814 .