Cholangiocarcinoma (CCA) is a heterogeneous disease arising from a complex interaction between host‐specific genetic background and multiple risk factors. Globally, CCA incidence rates exhibit ...geographical variation, with much higher incidence in parts of the Eastern world compared to the West. These differences are likely to reflect differences in geographical risk factors as well as genetic determinants. Of note, over the past few decades, the incidence rates of CCA appear to change and subtypes of CCA appear to show distinct epidemiological trends. These trends need to be interpreted with caution given the issues of diagnosis, recording and coding of subtypes of CCA. Epidemiological evidences suggest that in general population some risk factors are less frequent but associated with a higher CCA risk, while others are more common but associated with a lower risk. Moreover, while some risk factors are shared by intrahepatic and both extrahepatic forms, others seem more specific for one of the two forms. Currently some pathological conditions have been clearly associated with CCA development, and other conditions are emerging; however, while their impact in increasing CCA risk as single etiological factors has been provided in many studies, less is known when two or more risk factors co‐occur in the same patient. Moreover, despite the advancements in the knowledge of CCA aetiology, in Western countries about 50% of cases are still diagnosed without any identifiable risk factor. It is therefore conceivable that other still undefined etiologic factors are responsible for the recent increase of CCA (especially iCCA) incidence worldwide.
Biliary tract cancer (BTC) represents the second most frequently diagnosed primary liver cancer worldwide following hepatocellular carcinoma, and the overall survival of patients with unresectable ...disease remains poor. In recent years, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape of several malignancies with these agents, which have also been explored in advanced BTC, as monotherapy or in combination with other anticancer agents. However, clinical trials evaluating ICIs in BTC have shown conflicting results, and the clinical benefit provided by immunotherapy seems limited to a small subgroup of BTC patients. Thus, the identification of reliable predictors of the response to immunotherapy represents a significant challenge in this setting. This review provides an overview of the available evidence on the biomarkers predictive of the response to ICIs in patients with advanced BTC, especially focusing on programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), microsatellite instability (MSI), and other emerging biomarkers.
Research conducted during the past 30 years has increased our understanding of the mechanisms involved in colorectal cancer initiation and development. The findings have demonstrated the existence of ...at least three pathways: chromosomal instability, microsatellite instability and CpG island methylator phenotype. Importantly, new studies have shown that inflammation and microRNAs contribute to colorectal carcinogenesis. Recent data have demonstrated that several genetic and epigenetic changes are important in determining patient prognosis and survival. Furthermore, some of these mechanisms are related to patients' response to drugs, such as aspirin, which could be used for both chemoprevention and treatment in specific settings. Thus, in the near future, we could be able to predict disease behavior based on molecular markers found on tumors, and direct the best treatment options for patients.
•In 2010, the pivotal phase III ABC-02 trial established the doublet cisplatin plus gemcitabine as standard first-line therapy in treatment-naïve patients with advanced biliary tract cancer (BTC).•An ...impressive number of attempts has been made over time to improve clinical outcomes in patients receiving firs-line chemotherapy.•However, the combination of cisplatin plus gemcitabine remains the current standard of care in this setting.•Results of ongoing clinical trials on front-line setting will provide further information regarding the role of chemotherapy in combination with other anticancer agents such as immune checkpoint inhibitors in advanced BTC.
Biliary tract cancers (BTCs) include a heterogeneous group of highly aggressive hepatobiliary malignancies, representing the 3% of all gastrointestinal cancers and the second most frequent type of primary liver cancer after hepatocellular carcinoma. Ten years after the publication of the phase III, randomized, ABC-02 trial, the combination of cisplatin plus gemcitabine remains the standard first-line treatment for patients with advanced BTC. In the last decade, a large number of attempts has been made to improve the efficacy of the reference doublet by using novel drugs or adding a third agent to cisplatin-gemcitabine. Unfortunately, despite the addition of different cytotoxic drugs failed to improve clinical outcomes in several studies, recently published clinical trials have provided interesting results, and other first-line chemotherapy options are currently under investigation in randomized phase III studies. Moreover, recent years have witnessed the parallel emergence of molecularly targeted therapies and immune checkpoint inhibitors, with these novel agents having the potential to revolutionize the therapeutic algorithm of advanced BTC. In this review, we will provide an overview on first-line therapeutic opportunities currently available in the management of advanced BTCs, especially focusing on recently published data and ongoing clinical trials in this setting.
Systemic treatments have traditionally reported limited efficacy for biliary tract cancer (BTC), and although targeted therapies and immune checkpoint inhibitors have been found to play an ...increasingly important role in treatment, several questions remain unanswered, including the identification of biomarkers of response. The tumor microenvironment (TME) has recently attracted the attention of the BTC medical community, and is currently being studied due to its potential role in modulating response and resistance to systemic therapies, including immunotherapy. In this perspective article, we discuss available evidence regarding the interplay between TME, IDH inhibitors, and immunotherapy, providing rationale for the design of future clinical trials.
Immunotherapy has recently taken on an extremely important role in medical oncology, as first- or later-line treatment in several tumor types, and recent years have seen the emerging of clinical ...trials assessing immune checkpoint inhibitors (ICIs) in unresectable hepatocellular carcinoma (HCC).
Herein, we provide an overview of recently published studies exploring the dual immune checkpoint blockade or the combination of ICIs plus biological treatments as first-line treatment in HCC patients with advanced disease, especially focusing on the biological rationale behind these therapeutic strategies, and ongoing active and recruiting clinical trials.
Results of studies on monotherapy with ICIs have suggested that this strategy could be beneficial only in a minority of patients; conversely, the recently published IMbrave150 study has reported an overall survival benefit in HCC receiving the combination of atezolizumab plus bevacizumab compared to sorafenib as first-line treatment. A wide number of clinical trials is evaluating ICI-based combinations in advanced HCC, a strategy which is supported by robust preclinical and early-phase clinical data, and results of these studies are highly awaited.
During the last few years, the gut microbiota has gained increasing attention as a consequence of its emerging role as a modulator of the immune system. With the advent of the era of checkpoint ...inhibitors immunotherapy and adoptive cell transfer (ACT) in oncology, these findings became of primary relevance in light of experimental data that suggested the microbiota involvement as a plausible predictor of a good or poor response. These remarks justify the efforts to pinpoint the specific actions of the microbiota and to identify new strategies to favorably edit its composition.
Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of several malignancies, the role of immunotherapy in biliary tract cancer (BTC) is currently under ...investigation and ICIs are still looking for their niche in this setting. In this Editorial, we discuss recently published data regarding ICIs in BTC, with a particular focus in terms of selection of patients and biomarker-driven trials.
While sorafenib monotherapy represented the mainstay of medical treatment for advanced hepatocellular carcinoma (HCC) patients for more than a decade, novel agents and combination therapies have ...recently produced unprecedented paradigm shifts. The combination of lenvatinib plus pembrolizumab is now being evaluated as a front-line treatment in advanced HCC patients; early phase clinical trials have already reported promising results.
This paper reviews the combination of lenvatinib plus pembrolizumab for the treatment of advanced HCC. The preclinical rationale and completed and ongoing trials are examined and later, the authors reflect on biomarkers of predictive of response to immune-based combinations and future treatment decision-making on the basis of tolerability and clinical benefits provided by these novel therapeutics. A literature search was conducted in April 2021 of Pubmed/Medline, Cochrane library and Scopus databases; moreover, abstracts of international cancer meetings were reviewed.
The landscape of new agents and combinations continues to expand. Recently, immune-based combinations have reported important results in advanced HCC, as witnessed by the landmark IMbrave150 trial. Based on the promising results of early phase clinical trials, lenvatinib plus pembrolizumab has the potential to represent a novel treatment option in this setting.
•Unfortunately, although recent years have witnessed the advent of novel therapeutic options, patients with advanced cholangiocarcinoma (CCA) face a disappointing prognosis.•The fibroblast growth ...factor receptor (FGFR) inhibitor pemigatinib has reported remarkable results in the phase II FIGHT-202 trial.•Pemigatinib has received accelerated approval in April 2020 in the USA in previously treated CCA patients harboring FGFR2 fusions or other rearrangements.•However, several questions remain open, and further studies are warranted in this direction.•Results of ongoing clinical trials on pemigatinib and other selective FGFR inhibitors will provide further information regarding the role of these molecularly targeted therapies.
Cholangiocarcinoma (CCA) includes a heterogeneous group of malignancies with limited treatment options. Despite recent advances in medical oncology, the prognosis of CCA patients with metastatic disease remains poor, with a median overall survival of less than a year. In the last decade, notable efforts have been made by the CCA medical community in an attempt to improve clinical outcomes of patients, with the development of molecularly targeted therapies in this setting. Among these treatments, the fibroblast growth factor receptor (FGFR) 2 inhibitor pemigatinib has received accelerated approval in April 2020 by the US Food and Drug Administration (FDA) in CCA patients harboring FGFR2 gene fusions or other rearrangements, on the basis of the results of the FIGHT-202 trial, and thus, representing the first molecularly targeted therapy to be approved for the treatment of CCA. However, several issues remain, including the emergence of polyclonal mutations determining resistance to pemigatinib, the identification of biomarkers predictive of response, and the knowledge gaps regarding the role of other FGFR gene aberrations.
This review aims to provide an overview of recent development of pemigatinib, especially focusing on the results of the pivotal FIGHT-202 trial, the approval of this FGFR inhibitor, and the future challenges concerning the use of FGFR-directed treatments in CCA patients.
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