Cholangiocarcinoma (CCA) is a serious public health issue due to its insidious onset and dismal prognosis. The past few years have witnessed and highlighted the development of understanding and management of CCA. The combination of gemcitabine and cisplatin (GP) chemotherapy regimen with immunotherapy using immune checkpoint inhibitors has been considered the new standard first-line treatment alternative for advanced CCA. Notably, the proportion of patients with advanced CCA with targetable genetic mutations is approximately 40 %, and these patients may be considered for molecularly targeted therapy in the second-line treatment. In this review, we highlight the advances and progress in targeted therapies for advanced CCA, with special attention to data from Asian populations, including Chinese. In addition, we present in detail the phosphatase tension homolog (PTEN), a novel biomarker for both of first-line chemotherapy and second-line targeted therapy in advanced CCA, and its ability to forecast prognosis in patients with CCA. The mechanisms of rapid resistance to targeted agents warrant further investigation and address in light of the development of new targeted therapies. Precision medicine is gradually playing an increasing role in achieving optimal therapeutic outcomes.

A clinical trial of nab-paclitaxel plus capecitabine as a first-line treatment for advanced biliary tract cancers was conducted. We analyzed the development of systemic therapy recommended by the National Comprehensive Cancer Network guidelines and the development of nab-paclitaxel combination chemotherapy for advanced biliary tract cancers (BTCs) and concluded that nab-paclitaxel plus capecitabine is a promising first-line regimen for advanced BTCs.

Gallbladder cancer (GBC) is the most common and aggressive subtype of biliary tract cancer (BTC) and has a poor prognosis. A newly developed regimen of gemcitabine, cisplatin, and durvalumab shows promise for the treatment of advanced BTC. However, the efficacy of this treatment for GBC remains unclear.

In this report, we present a case in which the triple-drug regimen exhibited marked effectiveness in treating locally advanced GBC, thus leading to a long-term survival benefit. A 68-year-old man was diagnosed with locally advanced GBC, which rendered him ineligible for curative surgery. Following three cycles of therapy, a partial response was observed. After one year of combined therapy, a clinical complete response was successfully achieved. Subsequent maintenance therapy with durvalumab monotherapy resulted in a disease-free survival of 9 months for the patient. The patient experienced tolerable toxicities of reversible grade 2 nausea and fatigue. Tolerable adverse events were observed in the patient throughout the entirety of the treatment.

The combination of gemcitabine and cisplatin chemotherapy with durvalumab was proven to be an effective treatment approach for advanced GBC, with manageable adverse events. Further research is warranted to substantiate the effectiveness of the combined regimen in the context of GBC.

The current state of systemic therapy for advanced biliary tract cancer (BTC) has undergone significant changes. Currently, there are no clinical trials directly comparing various first-line systemic therapy regimens to each other, and these trials are unlikely to be conducted in the future. In this systematic review, after various abstracts and full-text articles published from the establishment of the database until October 2024 were searched, we included and analysed phase 3 clinical trials to evaluate the efficacy of different first-line systemic treatment regimens in advanced BTC. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines and a random effects model to pool the overall effects. Finally, seven low-risk-of-bias trials (with all of the trials representing first-line trials) were included. A total of 4033 patients were included in seven first-line trials. In terms of progression-free survival (PFS), network meta-analysis revealed that durvalumab + gemcitabine + cisplatin (GemCis) triple therapy, S-1 + GemCis triple therapy, and pembrolizumab + GemCis triple therapy were superior to GemCis. In terms of overall survival (OS), network meta-analysis revealed that durvalumab + GemCis triple therapy and pembrolizumab + GemCis triple therapy outperformed GemCis. According to the ranking of the P scores, durvalumab + GemCis triple therapy ranked first in PFS and second in OS. Therefore, the advantages of molecular immunotherapy have gradually become known, which suggests that future trials should focus on other potential combinations and molecular immunotargeted therapies.

Despite a rising incidence, biliary tract cancers (BTCs) are still considered a rare tumor entity. The disease's subtle clinical presentation and lack of effective early detection strategies often lead to a diagnosis at an advanced or unresectable stage, where curative options are limited.

This review provides an overview of current systemic therapies and emerging novel approaches for BTC. For decades, the combination of gemcitabine with cisplatin (GemCis) has been the standard of care for palliative treatment. However, since 2020, the diagnostic and therapeutic landscape for BTC has evolved considerably, not only in the first-line setting but also beyond, driven by the development of clinical trials exploring immunotherapy and molecularly targeted agents. Due to the high frequency of targetable genetic alterations in BTC patients, there is a growing emphasis on obtaining tissue or liquid biopsy samples to identify markers like microsatellite instability and other actionable oncogenic driver genes.

Early initiation of systemic therapies in combination with multimodal approaches is essential for maximizing survival outcomes in patients with BTC.

Systemic chemotherapy (SC) stands the only first-line treatment for advanced intrahepatic cholangiocarcinoma (iCCA) for the past few decades. Immune checkpoint inhibitors (ICIs) have been proved to provide additional benefit in disease control. However, oncological outcome of iCCA remains poor and awaits further improvement with new treatment modalities. Promising results have been observed in lenvatinib plus pembrolizumab (Len-P) as a second-line therapy in iCCA. This study aimed to explore the safety and efficacy of Len-P as a first-line therapy for iCCA patients in real-world clinical practice.

We retrospectively enrolled 133 patients with advanced iCCA who received Len-P or SC between May 2019 and May 2023. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were compared between the two groups.

There were 72 patients and 61 patients in the Len-P and SC groups, respectively. The median OS for the Len-P and SC groups was 16.3 and 17.8 months, respectively. The median PFS for the Len-P and SC groups was 8.9 and 11.4 months, respectively. There was no significant difference in ORR and DCR between the Len-P and SC groups (ORR: 22.2% vs. 23%; P=0.92; DCR: 69.4% vs. 77%; P=0.58). Additionally, the overall incidence of AEs was lower in the Len-P group than SC group. Low inflammation-based scores were indicative of favorable outcomes in patients undergoing Len-P therapy.

This study demonstrated that Len-P is promising for the treatment of advanced ICC, with highly improved safety. It emerges as a viable treatment alternative for advanced iCCA. Inflammation-based scores show potential utility in identifying individuals likely to benefit from Len-P therapy.

Biliary tract cancer (BTC) is a highly malignant tumor, with limited therapy regimens and short response duration. In this study, we aim to assess the efficacy and safety of the combination of camrelizumab, apatinib, and capecitabine as the first- or second-line treatment in patients with advanced BTC.

In this phase 2, nonrandomized, prospective study, eligible patients received camrelizumab (200 mg, d1, Q3W), apatinib (250 mg, qd, d1-d21, Q3W), and capecitabine (1000 mg/m², bid, d1-d14, Q3W) until trial discontinued. The primary endpoint was the objective response rate (ORR). The secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and safety.

From July 2019 to April 2023, we enrolled a total of 28 patients, of whom 14 patients were in the first-line treatment setting and 14 patients were in the second-line setting. At the data cutoff (April 30, 2023), the median follow-up duration was 18.03 months. Eight of 28 patients reached objective response (ORR: 28.57%), with an ORR of 50% and 7.1% for first-line and second-line treatment patients (P = .033). The median PFS was 6.30 months and the median OS was 12.80 months. Grade 3 or 4 adverse events (AEs) occurred in 9 (32.14%) patients, including elevated transaminase, thrombocytopenia, etc. No serious treatment-related AEs or treatment-related deaths occurred.

In this trial, the combination of camrelizumab, apatinib, and capecitabine showed promising antitumor activity and manageable toxicity in patients with advanced BTC, especially in the first-line setting.

NCT04720131.

Biliary tract carcinoma (BTC) is relatively rare and comprises a spectrum of invasive tumors arising from the biliary tree. The prognosis is extremely poor. The incidence of BTC is relatively high in Asian countries, and a high number of cases are diagnosed annually in China owing to the large population. Therefore, it is necessary to clarify the epidemiology and high-risk factors for BTC in China. The signs associated with BTC are complex, often require collaborative treatment from surgeons, endoscopists, oncologists, and radiation therapists. Thus, it is necessary to develop a comprehensive Chinese guideline for BTC.

This clinical practice guideline (CPG) was developed following the process recommended by the World Health Organization. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess the certainty of evidence and make recommendations. The full CPG report was reviewed by external guideline methodologists and clinicians with no direct involvement in the development of this CPG. Two guideline reporting checklists have been adhered to: Appraisal of Guidelines for Research and Evaluation (AGREE) and Reporting Items for practice Guidelines in Healthcare (RIGHT).

The guideline development group, which comprised 85 multidisciplinary clinical experts across China. After a controversies conference, 17 clinical questions concerning the prevention, diagnosis, and treatment of BTC were proposed. Additionally, detailed descriptions of the surgical principles, perioperative management, chemotherapy, immunotherapy, targeted therapy, radiotherapy, and endoscopic management were proposed.

The guideline development group created a comprehensive Chinese guideline for the diagnosis and treatment of BTC, covering various aspects of epidemiology, diagnosis, and treatment. The 17 clinical questions have important reference value for the management of BTC.

Oxaliplatin- and fluoropyrimidine-based triplet regimens have demonstrated feasibility and efficacy in the treatment of upper gastrointestinal (UGI) cancers. Herein, we evaluate the feasibility and preliminary efficacy of biweekly nab-paclitaxel plus oxaliplatin and S-1/leucovorin (SOLAR) in chemonaïve UGI cancers.

A 3 + 3 phase 1 study was conducted to determine the maximal tolerated dose (MTD) of oxaliplatin in SOLAR (nab-paclitaxel [150 mg/m2 in D1], oxaliplatin [60, 75, or 85 mg/m2 in D1], and oral S-1/leucovorin [35 mg/m2 and 30 mg bid from D1 to D7]). The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety.

Thirteen and 6 accruals were in the dose-escalation and MTD expansion cohorts, respectively. One of 6 patients at level III experienced dose-limiting toxicity (grade 3 diarrhea), which revealed that the MTD of oxaliplatin was 85 mg/m2. After a mean of 15.9 cycles of treatment, the most common treatment-related grade 3/4 toxicities were neutropenia (57.9%) and diarrhea (21.1%). The ORR was 63.2%. The median PFS and OS were 12.5 and 24.7 months, respectively.

The current study revealed the MTD of oxaliplatin and demonstrated the preliminary efficacy of SOLAR in UGI cancers, which deserves further investigation.

NCT03162510.

Intrahepatic cholangiocarcinoma (ICC) remains a significant challenge in cancer therapy, especially due to its resistance to established treatments like Gemcitabine, necessitating novel therapeutic approaches.

This study utilized Gemcitabine-resistant cell lines, patient-derived organotypic tumor spheroids (PDOTs), and patient-derived xenografts (PDX) to evaluate the effects of Saikosaponin-a (SSA) on ICC cellular proliferation, migration, apoptosis, and its potential synergistic interaction with Gemcitabine. Techniques such as transcriptome sequencing, Luciferase reporter assays, and molecular docking were employed to unravel the molecular mechanisms.

SSA exhibited antitumor effects in both in vitro and PDX models, indicating its considerable potential for ICC treatment. SSA markedly inhibited ICC progression by reducing cellular proliferation, enhancing apoptosis, and decreasing migration and invasion. Crucially, it augmented Gemcitabine's efficacy by targeting the p-AKT/BCL6/ABCA1 signaling pathway. This modulation led to the downregulation of p-AKT and suppression of BCL6 transcriptional activity, ultimately reducing ABCA1 expression and enhancing chemosensitivity to Gemcitabine. Additionally, ABCA1 was validated as a predictive biomarker for drug resistance, with a direct correlation between ABCA1 expression levels and the IC50 values of various small molecule drugs in ICC gene profiles.

This study highlights the synergistic potential of SSA combined with Gemcitabine in enhancing therapeutic efficacy against ICC and identifies ABCA1 as a key biomarker for drug responsiveness. Furthermore, the introduction of the novel PDOTs microfluidic model provides enhanced insights into ICC research. This combination strategy may provide a novel approach to overcoming treatment challenges in ICC.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common malignant primary liver cancer. iCCA may develop on an underlying chronic liver disease and its incidence is growing in relation with the epidemics of obesity and metabolic diseases. In contrast, perihilar cholangiocarcinoma (pCCA) may follow a history of chronic inflammatory diseases of the biliary tract. The initial management of CCAs is often complex and requires multidisciplinary expertise. The French Association for the Study of the Liver wished to organize guidelines in order to summarize the best evidence available about several key points in iCCA and pCCA. These guidelines have been elaborated based on the level of evidence available in the literature and each recommendation has been analysed, discussed and voted by the panel of experts. They describe the epidemiology of CCA as well as how patients with iCCA or pCCA should be managed from diagnosis to treatment. The most recent developments of personalized medicine and use of targeted therapies are also highlighted.

Re-resection is recommended for patients with incidental gallbladder carcinoma (iGBC) at T1b stage and above. It is unclear whether continuation of laparoscopic re-resection (CLR) for patients with intraoperatively detected iGBC (IDiGBC) is more beneficial to short- and long-term clinical outcomes than with conversion to radical extensive-resection (RER).

This single-centre, retrospective cohort study of patients with iGBC was conducted between June 2006 and August 2021. Patients who underwent immediate reresection for T1b or higher ID-iGBC were enrolled. Propensity score matching (PSM) was used to match the two groups (CLR and RER) of patients, and differences in clinical outcomes before and after matching were analyzed.

A total of 102 patients with ID-iGBC were included in this study. 58 patients underwent CLR, and 44 underwent RER. After 1:1 propensity score matching, 56 patients were matched to all baselines. Patients in the RER group had a lower total postoperative complication rate, lower pulmonary infection rate, and shorter operation time than those in the CLR group did. Kaplan-Meier analysis showed that the overall survival rate of patients who underwent CLR was significantly lower than that of patients who underwent RER. Multivariate analysis showed that CLR, advanced T stage, lymph node positivity, and the occurrence of postoperative ascites were adverse prognostic factors for the overall survival of patients.

Patients with ID-iGBC who underwent RER had fewer perioperative complications and a better prognosis than those who underwent CLR. For patients with ID-iGBC, conversion to radical extensive-resection appears to be a better choice.

The anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking.

ABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing.

A total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48-0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62-1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival.

This retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.

Hepato-Pancreato-Biliary (HPB) malignancies constitute a highly aggressive group of cancers that have a dismal prognosis. Patients not amenable to curative intent surgical resection are managed with systemic chemotherapy which, however, confers little survival benefit. Antibody-Drug Conjugates (ADCs) are tripartite compounds that merge the intricate selectivity and specificity of monoclonal antibodies with the cytodestructive potency of attached supertoxic payloads. In view of the unmet need for drugs that will enhance the survival rates of HPB cancer patients, the assessment of ADCs for treating HPB malignancies has become the focus of extensive clinical and preclinical investigation, showing encouraging preliminary results. In the current review, we offer a comprehensive overview of the growing body of evidence on ADC approaches tested for HPB malignancies. Starting from a concise discussion of the functional principles of ADCs, we summarize here all available data from preclinical and clinical studies evaluating ADCs in HPB cancers.

Biliary tract cancers (BTCs) are a heterogeneous group of tumors with high malignancy, poor prognosis, and limited treatment options.

To explore the efficacy and safety of nab-paclitaxel plus capecitabine as first-line treatment for advanced and metastatic BTCs.

This open-label, non-randomized, double-center, phase II clinical trial recruited systemic therapy-naive patients with unresectable or metastatic BTCs between April 2019 and June 2022 at Beijing Cancer Hospital and the First Hospital of China Medical University. Eligible patients were administered nab-paclitaxel (150 mg/m2, day 1) and capecitabine (2000 mg/m2, twice daily, days 1-7) in 14-day cycles until experiencing intolerable toxicity or disease progression. The primary outcome was the objective response rate (ORR). The secondary outcomes included the disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety.

A total of 44 patients successfully completed the trial, with a median age of 64.00 years (interquartile range, 35.00-76.00), and 26 (59.09%) were females. Tumor response assessment was impeded for one patient due to premature demise from tumor hemorrhage. Among the remaining 43 patients undergoing at least one imaging assessment, the ORR was 23.26% [95% confidence interval (CI): 11.80%-38.60%], and the DCR was 69.77% (95%CI: 53.90%-82.80%). The median OS was 14.1 months (95%CI: 8.3-19.9), and the median PFS was 4.4 months (95%CI: 2.5-6.3). A total of 41 patients (93.18%) experienced at least one adverse event (AE), with 10 patients (22.73%) encountering grade ≥ 3 AEs, and the most frequent AEs of any grade were alopecia (79.50%), leukopenia (54.55%), neutropenia (52.27%), and liver dysfunction (40.91%), and no treatment-related deaths were documented.

Nab-paclitaxel plus capecitabine may be an effective and safe first-line treatment strategy for patients with advanced or metastatic BTCs.

Cholangiocarcinoma (CCA) is a hepatic malignancy that has a rapidly increasing incidence. CCA is anatomically classified into intrahepatic (iCCA) and extrahepatic (eCCA), which is further divided into perihilar (pCCA) and distal (dCCA) subtypes, with higher incidence rates in Asia. Despite its rarity, CCA has a low 5-year survival rate and remains the leading cause of primary liver tumor-related death over the past 10-20 years. The systemic therapy section discusses gemcitabine-based regimens as primary treatments, along with oxaliplatin-based options. Second-line therapy is limited but may include short-term infusional fluorouracil (FU) plus leucovorin (LV) and oxaliplatin. The adjuvant therapy section discusses approaches to improve overall survival (OS) post-surgery. However, only a minority of CCA patients qualify for surgical resection. In comparison to adjuvant therapies, neoadjuvant therapy for unresectable cases shows promise. Gemcitabine and cisplatin indicate potential benefits for patients awaiting liver transplantation. The addition of immunotherapies to chemotherapy in combination is discussed. Nivolumab and innovative approaches like CAR-T cells, TRBAs, and oncolytic viruses are explored. We aim in this review to provide a comprehensive report on the systemic and locoregional therapies for CCA.

Limited 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.

Patient 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.

The 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.

In 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.

The incidence of intrahepatic cholangiocarcinoma (IHCCA) is rising around the world. The disease is becoming a major global health issue. Conventionally, most patients with cholangiocarcinoma present with advanced disease and systemic therapy is the mainstay of treatment. This review discusses recent advances in systemic treatments for patients with IHCCA.

The addition of durvalumab to a gemcitabine plus cisplatin regimen has significantly improved overall survival in the phase 3 TOPAZ-1 trial and is currently recommended as a standard first-line treatment. The phase 3 ABC-06 and phase 2b NIFTY trials have shown the benefit of second-line fluoropyrimidine plus oxaliplatin, and fluoropyrimidine plus nanoliposomal irinotecan, respectively. They have provided a treatment option for patients without actionable alterations who progressed to first-line therapy. For patients with actionable genomic alterations, including FGFR2 rearrangement, IDH1 mutation, BRAF mutation, and ERBB2 amplification, targeted agents have shown encouraging efficacy in several phase 2-3 trials, and are recommended as subsequent treatments. Immune checkpoint inhibitors are being investigated for the treatment of previously treated patients, although only a small proportion of patients showed durable responses.

Recent advances in systemic treatments have improved clinical outcomes in patients with advanced IHCCA. However, most patients eventually show resistance to the treatment, and tumor progression occurs within a year. Indeed, there should be further efforts to improve the outcomes of patients with advanced IHCCA.

Systemic chemotherapy (SYS) is the first-line treatment of unresectable intrahepatic cholangiocarcinoma (ICC). However, the survival benefit of SYS is still limited. This study compared the efficacy and safety of patients with unresectable ICC treated with transarterial chemoembolization (TACE) plus SYS to SYS alone.

The multicenter retrospective cohort study included patients aged ≥ 18 years old with pathologically diagnosed ICC. Patients with unmeasurable lesions, not receiving SYS treatment, Child-Pugh grade C, Eastern Cooperative Oncology Group performance status score of 3 or higher, prior liver resection, incomplete medical information, or discontinuation of the first SYS treatment were excluded. Data collection was mainly from the hospital system, and the survival outcome of patients was obtained through follow-up. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Propensity score matching at a 1:1 ratio using the nearest neighbor matching algorithm was performed to reduce selection bias between the TACE plus SYS and SYS alone groups. The Cox proportional hazards model was used to identify prognostic factors associated with OS and to estimate their hazard ratios. Modified Response Evaluation Criteria in Solid Tumors criteria were utilized to evaluate the response of tumors to therapy.

Between June 2016 and February 2023, 118 unresectable ICC patients from three hospitals were included in this study. Of them, 37 were in the TACE plus SYS group and 81 were in the SYS alone group. The median OS in the combination group was 11.3 months, longer than the 6.4 months in the SYS alone group (P = 0.011). A greater objective response rate (ORR) and disease control rate (DCR) were observed in the combination group than in the SYS alone group (ORR, 48.65 vs. 6.17%, P < 0.001; DCR, 89.19 vs. 62.96%, P = 0.004). There were 16 patients in each group after matching, and the matched results remained consistent regarding OS and tumor response. Adverse events (AEs) were similar in the two groups after matching.

Compared to SYS alone, the combination treatment of TACE plus SYS was more effective than SYS alone in improving OS, ORR, and DCR without any significant increase in AEs. TACE plus SYS may be a viable treatment option for patients with unresectable ICC.

Cholangiocarcinomas (CCA) pose a complex challenge in oncology due to diverse etiologies, necessitating tailored therapeutic approaches. This review discusses the risk factors, molecular pathology, and current therapeutic options for CCA and explores the emerging strategies encompassing targeted therapies, immunotherapy, novel compounds from natural sources, and modulation of gut microbiota. CCA are driven by an intricate landscape of genetic mutations, epigenetic dysregulation, and post-transcriptional modification, which differs based on geography (e.g., for liver fluke versus non-liver fluke-driven CCA) and exposure to environmental carcinogens (e.g., exposure to aristolochic acid). Liquid biopsy, including circulating cell-free DNA, is a potential diagnostic tool for CCA, which warrants further investigations. Currently, surgical resection is the primary curative treatment for CCA despite the technical challenges. Adjuvant chemotherapy, including cisplatin and gemcitabine, is standard for advanced, unresectable, or recurrent CCA. Second-line therapy options, such as FOLFOX (oxaliplatin and 5-FU), and the significance of radiation therapy in adjuvant, neoadjuvant, and palliative settings are also discussed. This review underscores the need for personalized therapies and demonstrates the shift towards precision medicine in CCA treatment. The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. In the future, extensive translational research efforts are imperative to bridge existing gaps and optimize therapeutic strategies to improve therapeutic outcomes for this complex malignancy.

A regimen of gemcitabine, cisplatin, and nab-paclitaxel (GPA) has shown promising results in patients with advanced biliary tract cancer (aBTC).

This study aimed to evaluate the benefit of GPA compared to a regimen of gemcitabine plus cisplatin (GP) in patients with aBTC.

Retrospective study.

Patients with aBTC who received first-line chemotherapy with GPA or GP regimen at the Samsung Medical Center between July 2020 and June 2022 were included. The primary endpoint was progression-free survival (PFS).

In all, 37 patients were treated with GPA and 43 patients with GP. The GPA group showed significantly longer median PFS [12.0 months (95% CI, 7.2-16.8)] compared to the GP group [5.5 months (95% CI, 3.7-7.4; p = 0.007)]. The median overall survival (OS) was also longer in the GPA group [18.7 months (95% CI, 13.7-23.7)] than in the GP group [10.7 months (95% CI, 1.5-19.9); p = 0.021]. First-line chemotherapy with GPA was associated with longer PFS, while metastatic disease at initial diagnosis and post-treatment increase in CA 19-9 level were associated with worse PFS.

The GPA regimen improved the PFS of patients with aBTC compared to the GP regimen but showed no significant benefit in terms of OS after adjusting for confounding variables. Further large-scale studies are required to establish optimal indications for GPA.

Cholangiocarcinoma (CC) is a heterogeneous group of malignancies that originates at any point along the biliary tree. CC is an uncommon malignancy as it represents approximately 3% of all gastrointestinal malignancies, though its global incidence is rising. CC can often be asymptomatic in its early stages and as a result, it is frequently diagnosed in later stages, leading to challenges in clinical management.

The prognosis of advanced biliary tract cancer (BTC) patients remains poor due to limited efficacy of chemotherapy and difficulties in management. Thus, prediction of survival is crucial for the clinical management of advanced BTC. The aim was to develop and validate a nomogram to predict 6-month and 12-month survival in advanced BTC patients treated with chemotherapy. A multivariable Cox regression model was used to construct a nomogram in a training set (JCOG1113, a phase III trial comparing gemcitabine plus S-1 [GS] and gemcitabine plus cisplatin, n = 351). External validity of the nomogram was assessed using a test set (JCOG0805, a randomized, phase II trial comparing GS and S-1 alone, n = 100). Predictive performance was assessed in terms of discrimination and calibration. The constructed nomogram included lymph node metastasis, liver metastasis, carbohydrate antigen 19-9, carcinoembryonic antigen, albumin, and C-reactive protein. Uno's concordance index was 0.661 (95% confidence interval [CI] 0.629-0.696) in the training set and 0.640 (95% CI 0.566-0.715) in the test set. The calibration plots for 6-month and 12-month survival showed good agreement in the two analysis sets. The present nomogram can facilitate prediction of the prognosis of advanced BTC patients treated with chemotherapy and help clinicians' prognosis-based decision-making.

Background: Systemic chemotherapy (SC) remains the only first-line treatment for unresectable intrahepatic cholangiocarcinoma (iCCA). Hepatic arterial infusion chemotherapy (HAIC) has been recently proven to be effective in managing hepatocellular carcinoma (HCC). Hence, our study aims to investigate the safety and efficacy of HAIC in treating unresectable iCCA patients. Methods: We reviewed 146 patients with unresectable iCCA who had received HAIC or SC between March 2016 and March 2022 in a retrospective manner. Outcomes of patients and safety were compared between the HAIC and SC groups. Results: There were 75 and 71 patients in the HAIC and SC groups, respectively. The median OS in the HAIC and SC groups was 18.0 and 17.8 months (p = 0.84), respectively. The median PFS in the HAIC and SC groups was 10.8 and 11.4 months (p = 0.59), respectively. However, the HAIC group had significantly longer intrahepatic progression-free survival (IPFS) than the SC group (p = 0.035). The median IPFS in the HAIC and SC groups was 13.7 and 11.4 months, respectively. According to the OS (p = 0.047) and PFS (p = 0.009), single-tumor patients in the HAIC group appeared to benefit more. In addition, the overall incidence of adverse events (AEs) was lower in the HAIC group than that in the SC group. Conclusion: Our study revealed that HAIC was a safe and effective therapeutic regimen for unresectable iCCA with better intrahepatic tumor control when compared to SC. Meanwhile, patients with single tumor were more likely to benefit from HAIC than SC.

Randomised controlled trials (RCTs) are usually considered the highest level of evidence for clinical practice. Patients assigned to control arm in RCTs should always receive the best available treatments to protect participants while also allowing for proper interpretation and applicability of study results. Here we analysed RCTs published in oncology between 2017 and 2021 to describe the frequency of suboptimal control arms.

We identified phase III studies testing active treatments in patients with solid tumours among 11 major oncology journals. Each control arm was analysed, and the standard of care was determined according to international guidelines and scientific evidence at accrual beginning and until accrual completion. We identified studies with suboptimal control arm from the beginning (type 1) and studies with an initially optimal control arm which became outdated during the accrual period (type 2).

This analysis included 387 studies. Forty-three (11.1%) control arms were judged as suboptimal: 24 (6.2%) type 1 and 19 (4.9%) type 2. These rates were higher in industry-sponsored compared to academic trials: 9.3% versus 1.9% for type 1 (p = 0.003); 7.9% versus 0.6% for type 2 (p = 0.001). Rates of suboptimal control arms were higher in studies with positive results: 8.1% versus 4.0% for type 1 (p = 0.09); 7.6% versus 1.7% for type 2 (p = 0.007).

Many trials have suboptimal control arms, even in journals with high-impact factors, leading to suboptimal treatment of control patients and biased evaluation of trial results.

Surgery remains the preferred treatment option for early-stage gallbladder cancer (GBC). According to the anatomical position of the primary tumor, accurate preoperative stage and strict control of surgical indications, appropriate surgical strategies are selected to achieve the optimal surgical effect. However, most patients have already been at the locally advanced stage or the tumor has metastasized at the initial diagnosis. The postoperative recurrence rate and 5-year survival rate remain unsatisfactory even after radical resection for gallbladder cancer. Hence, there is an urgent need for more treatment options, such as neoadjuvant therapy, postoperative adjuvant therapy and first-line and second-line treatments of local progression and metastasis, in the whole-course treatment management of gallbladder cancer patients. In recent years, the application of molecular targeted drugs and immunotherapy has brought greater hope and broader prospects for the treatment of gallbladder cancer, but their effects in improving the prognosis of patients still lack sufficient evidence-based medicine evidence, so many problems should be addressed by further research. Based on the latest progress in gallbladder cancer research, this review systematically analyzes the treatment trends of gallbladder cancer.

Malignant tumors of the biliary system are characterized by a high degree of malignancy and strong invasiveness, and they are usually diagnosed at late stages with poor prognosis. For patients with advanced biliary tract cancer, chemotherapy and targeted therapy are two of the options available to improve prognosis and delay tumor progression. This study aimed to comprehensively evaluate the safety and effectiveness of various chemotherapy schemes for the treatment of advanced biliary tract cancer in published systematic reviews and meta-analyses (SRoMAs).

An umbrella review method was adopted, which aims to summarize the existing evidence from multiple studies around a research topic. SRoMAs up to April 9, 2022, were identified using PubMed, Web of Science, the Cochrane database, and manual screening. Eligible studies were screened according to inclusion and exclusion criteria. This study had been registered at PROSPERO (CRD42022324548). For each eligible study, we extracted the data of general characteristics and the main findings. The methodological quality of the included studies were assessed by the AMSTAR2 scale, and the quality of evidence was evaluated by the GRADE tools.

A total of 1833 articles were searched; 14 unique articles with 94 outcomes were identified by eligibility criteria. The incidence of skin rash (RR = 18.11, 95% CI 5.13-63.91, GRADE: Moderate) and diarrhea (RR = 2.48, 95% CI 1.2-5.10, GRADE: Moderate) was higher in patients receiving gemcitabine-based chemotherapy plus targeted therapy than in patients receiving gemcitabine monotherapy. The number of patients receiving gemcitabine-based chemotherapy who developed leukopenia (OR = 7.17, 95% CI 1.43-36.08, GRADE: Moderate), anemia (OR = 7.04, 95% CI 2.59-19.12, GRADE: High), thrombocytopenia (RR = 2.45, 95% CI 1.39-4.32, GRADE: Moderate), and neutropenia (RR = 3.30, 95% CI 1.04-10.50, GRADE: Moderate) was significantly higher than that of patients who received gemcitabine-free regimens. In addition, patients receiving S-1 monotherapy had significantly better ORR (RR = 2.46, 95% CI 1.27-4.57, GRADE: Moderate) than patients receiving S-1 + gemcitabine. Patients receiving fluoropyrimidine-based chemotherapy had longer OS (HR = 0.83, 95% CI 0.7-0.99, GRADE: Moderate), higher DCR (0R = 5.18, 95% CI 3.3-10.23, GRADE: Moderate), and higher ORR (0R = 3.24, 95% CI 1.18-8.92, GRADE: Moderate) compared with patients who received 5-FU/LV monotherapy or supportive therapy. Surprisingly, we found evidence that gemcitabine-based chemotherapy did not improve postoperative patients' OS (HR = 0.91, 95% CI 0.74-1.12, GRADE: Moderate) when compared with best supportive care.

This study comprehensively evaluated the safety and efficacy of chemotherapy or targeted therapy regimens for advanced biliary tract cancer and found 11 outcomes with "Moderate" or "High" levels; however, most of the outcomes were still at "low" or "very low" levels. More randomized controlled studies are needed in the future to further summarize high levels of evidence.

The prognosis of biliary tract cancer (BTC) remains unsatisfactory. This single-arm, phase II clinical trial (ChiCTR2000036652) investigated the efficacy, safety, and predictive biomarkers of sintilimab plus gemcitabine and cisplatin as the first-line treatment for patients with advanced BTCs. The primary endpoint was overall survival (OS). Secondary endpoints included toxicities, progression-free survival (PFS), and objective response rate (ORR); multi-omics biomarkers were assessed as exploratory objective. Thirty patients were enrolled and received treatment, the median OS and PFS were 15.9 months and 5.1 months, the ORR was 36.7%. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Predefined biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations or loss-of-function mutations in chromatin remodeling genes presented better tumor response and survival outcomes. Furthermore, transcriptome analysis revealed a markedly longer PFS and tumor response were associated with higher expression of a 3-gene effector T cell signature or an 18-gene inflamed T cell signature. Sintilimab plus gemcitabine and cisplatin meets pre-specified endpoints and displays acceptable safety profile, multiomics potential predictive biomarkers are identified and warrant further verification.

Cholangiocarcinoma (CCA) is a neoplasm with high mortality that represents 15% of all primary liver tumors. Its worldwide incidence is on the rise, and despite important advances in the knowledge of molecular mechanisms, diagnosis, and treatment, overall survival has not substantially improved in the last decade. Surgical resection remains the cornerstone therapy for CCA. Unfortunately, complete resection is only possible in less than 15-35% of cases, with a risk of recurrence greater than 60%. Liver transplantation (LT) has been postulated as an effective therapeutic strategy in those intrahepatic CCA (iCCA) smaller than 3 cm. However, the low rate of early diagnosis in non-resectable patients justifies the low applicability in clinical practice. The evidence regarding LT in locally advanced iCCA is scarce and based on small, retrospective, and, in most cases, single-center case series. In this setting, the response to neoadjuvant chemotherapy could be useful in identifying a subgroup of patients with biologically less aggressive tumors in whom LT may be successful. The results of LT in pCCA are promising, however, we need a very careful selection of patients and adequate experience in the transplant center. Locoregional therapies may be relevant in unresectable, liver-only CCA. In iCCA smaller than 2 cm, particularly those arising in patients with advanced chronic liver disease in whom resection or LT may not be feasible, thermal ablation may become a reliable alternative. The greatest advances in the management of CCA occur in systemic treatment. Immunotherapy associated with chemotherapy has emerged as the gold standard in the first-line treatment. Likewise, the most encouraging results have been obtained with targeted therapies, where the use of personalized treatments has shown high rates of objective and durable tumor response, with clear signs of survival benefit. In conclusion, the future of CCA treatment seems to be marked by the development of new treatment strategies but high-quality, prospective studies that shed light on their use and applicability are mandatory.

Cholangiocarcinoma (CCA) is a diverse group of epithelial cancers that affect the biliary tree. The incidence of CCA is low in Western countries but significantly higher in endemic regions such as China and Thailand. Various risk factors contribute to the development of CCA. Recent studies have revealed molecular alterations in biliary tract cancers, providing insights into cholangiocarcinogenesis and potential targeted therapies. Surgical resection is the primary curative treatment for CCA. Adjuvant chemotherapy has been extensively studied, and some regimens have proven to be beneficial. Neoadjuvant chemotherapy has shown potential benefits in select cases, but its role remains controversial. In advanced stages, chemotherapy is the standard of care, and molecular profiling has identified potential targets such as FGFR, IDH1, HER2, and other tumor-agnostic therapies. Immunotherapy has demonstrated limited benefit in advanced CCA. This chapter provides an overview of the current evidence and ongoing research evaluating various chemotherapy regimens, targeted therapies, and immunotherapies across different stages of CCA.

Gallbladder cancer (GBC) is a relatively infrequent but highly lethal cancer with a poor prognosis. Management remains challenging and controversial, and most patients are diagnosed at an advanced stage. However, with the progressive advances in the use of immunotherapies, new treatment modalities are being implemented. In September 2022, the US FDA approved durvalumab (a PD-L1 inhibitor) in combination with chemotherapy for adult patients with locally advanced or metastatic GBC. This groundbreaking news is the first FDA approval for the use of immunotherapy in biliary tract cancers. This article reviews the newest advances and trials regarding immunotherapy for GBC.

Biliary tract cancers (BTCs) are a heterogeneous group of tumors that are rare in Western countries and have a poor prognosis. Three subgroups are defined by their anatomical location (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder carcinoma) and exhibit distinct clinical, molecular, and epidemiologic characteristics. Most patients are diagnosed at an advanced disease stage and are not eligible for curative-intent resection. In addition to first- and second-line chemotherapies (CisGem and FOLFOX, respectively), biologic therapies are now available that target specific genomic alterations identified in BTC. To date, targets include alterations in the genes for isocitrate dehydrogenase (IDH) 1, fibroblast growth factor receptor (FGFR) 2, v-raf murine sarcoma viral oncogene homolog B1 (BRAF), human epidermal growth factor receptor 2 (HER2 or ERRB2), and neurotrophic tyrosine receptor kinase (NTRK), and for those leading to DNA mismatch repair deficiency. Therapies targeting these genomic alterations have demonstrated clinical benefit for patients with BTC. Despite these therapeutic advancements, genomic diagnostic modalities are not widely used in France, owing to a lack of clinician awareness, local availability of routine genomic testing, and difficulties in obtaining health insurance reimbursement. The addition of durvalumab, a monoclonal antibody targeting the immune checkpoint programmed cell death ligand-1, to CisGem in the first-line treatment of advanced BTC has shown an overall survival benefit in the TOPAZ-1 trial. Given the high mortality rates associated with BTC and the life-prolonging therapeutic options now available, it is hoped that the data presented here will support updates to the clinical management of BTC in France.

Gemcitabine/cisplatin (GC) combination therapy has been the standard palliative chemotherapy for patients with advanced biliary tract cancer (BTC). No randomized clinical trials have been able to demonstrate the survival benefit over GC during the past decade. In our previous phase II trial, adding S-1 to GC (GCS) showed promising efficacy and we aimed to determine whether GCS could improve overall survival compared with GC for patients with advanced BTC.

We performed a mulitcenter, randomized phase III trial across 39 centers. Enrolled patients were randomly allocated (1:1) to either the GCS or GC arm. The GCS regimen comprised gemcitabine (1000 mg/m² ) and cisplatin (25 mg/m² ) infusion on day 1 and 80 mg/m² of S-1 on days 1-7 every 2 weeks. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS), response rate (RR), and adverse events (AEs). This study is registered with Clinical trial identification: NCT02182778.

Between July 2014 and February 2016, 246 patients were enrolled. The median OS and 1-year OS rate were 13.5 months and 59.4% in the GCS arm and 12.6 months and 53.7% in the GC arm, respectively (hazard ratio [HR] 0.79, 90% confidence interval [CI]: 0.628-0.996; P = .046 [stratified log-rank test]). Median PFS was 7.4 months in the GCS arm and 5.5 months in the GC arm (HR 0.75, 95% CI: 0.577-0.970; P = .015). RR was 41.5% in the GCS arm and 15.0% in the GC arm. Grade 3 or worse AEs did not show significant differences between the two arms.

GCS is the first regimen which demonstrated survival benefits as well as higher RR over GC in a randomized phase III trial and could be the new first-line standard chemotherapy for advanced BTC. To exploit the advantage of its high RR, GCS is now tested in the neoadjuvant setting in a randomized phase III trial for potentially resectable BTC.