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Research Progress of Biliary Tract Cancers

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 33750

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Dr. Amit Mahipal

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Guest Editor

Department of Oncology, Mayo Clinic, Rochester, MN, USA
Interests: biliary tract cancers; cholangiocarcinoma; hepatocellular cancer; pancreatic cancer; drug development
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Biliary tract cancers are uncommon gastrointestinal malignancies with dismal prognosis. Surgical resection and liver transplantation remains the only curative modality at this time. However, the majority of the patients present at advanced stage rendering systemic therapy as the only treatment option. A significant progress has been made in understanding of cholangiocarcinoma and gallbladder tumorigenesis and molecular markers over the last decade. The role of radiation therapy and liver directed therapies remains undefined for patients with cholangiocarcinoma. Gemcitabine and cisplatin combination chemotherapy remains the only approved standard of care treatment for biliary tract cancers. There are no consensus guidelines on helping to choose a second line option with most of the data being reported from small phase II trials.

This issue will cover topics on current standard of care treatment, chemotherapy, targeted treatment based on molecular markers, immunotherapy, and novel drug development for this difficult to treat disease.

Dr. Amit Mahipal
Guest Editor

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Keywords

cholangiocarcinoma
gallbladder cancer
targeted treatment

Published Papers (11 papers)

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Editorial

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3 pages, 184 KiB

Open AccessEditorial

Research Progress of Biliary Tract Cancers

by Lionel Aurelien A. Kankeu Fonkoua and Amit Mahipal

Cancers 2021, 13(4), 919; https://doi.org/10.3390/cancers13040919 - 22 Feb 2021

Viewed by 1387

Abstract

This series of nine articles (three original articles, six reviews) is presented by international leaders in biliary tract cancers (BTC) [...] Full article

(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)

Research

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10 pages, 243 KiB

Open AccessArticle

Aspirin and Statin Use and the Risk of Gallbladder Cancer

by Kritika Prasai, Sri Harsha Tella, Siddhartha Yadav, Anuhya Kommalapati, Kristin Mara, Mohamed Mady, Mohamed A. Hassan, Nicha Wongjarupong, Natalia Rodriguez-Payan, Mitesh Borad, Tushar Patel, Lewis R. Roberts and Amit Mahipal

Cancers 2021, 13(5), 1186; https://doi.org/10.3390/cancers13051186 - 09 Mar 2021

Cited by 4 | Viewed by 2188

Abstract

Aspirin and statin drugs have been associated with reduced risk of several gastrointestinal cancers, but their association with gallbladder cancer (GBC) has not been well established. We evaluated the association of aspirin and statins with the risk of GBC. Patients with GBC managed at Mayo Clinic between 2000 and 2019 were matched 1:2 with a general patient pool by age and sex. Univariable and multivariable logistic regression models were used to assess associations between GBC and aspirin or statin use. The analysis included 795 cases and 1590 controls, with a median age of 67 years. Aspirin or statin use alone or in combination was higher in controls (p < 0.001). Univariate analysis showed that the use of aspirin [odds ratio (OR): 0.11; 95%CI: 0.08–0.15] or statins (OR: 0.29; 95%CI: 0.20–0.40) and their combined use (OR: 0.18; 95%CI: 0.13–0.24) was associated with lower risk of GBC. Multivariable analysis revealed that aspirin (OR: 0.12; 95%CI: 0.09–0.16) and combined statins and aspirin (OR: 0.46; 95%CI: 0.31–0.67) were associated with lower risk of GBC. Aspirin alone or in combination with statins is associated with a strongly reduced risk of GBC. Further prospective studies are needed to confirm these results and to elucidate their mechanisms. Full article

(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)

16 pages, 3455 KiB

Open AccessArticle

Efficacy and Safety of CAP7.1 as Second-Line Treatment for Advanced Biliary Tract Cancers: Data from a Randomised Phase II Study

by Ulrich-Frank Pape, Stefan Kasper, Johannes Meiler, Marianne Sinn, Arndt Vogel, Lothar Müller, Oswald Burkhard, Karel Caca, Steffen Heeg, Petra Büchner-Steudel, Victor Rodriguez-Laval, Anja A Kühl, Ruza Arsenic, Holger Jansen, Peter Treasure and Nalân Utku

Cancers 2020, 12(11), 3149; https://doi.org/10.3390/cancers12113149 - 27 Oct 2020

Cited by 2 | Viewed by 2766

Abstract

CAP7.1 is a novel topoisomerase II inhibitor, converted to active etoposide via carboxylesterase 2 (CES2), with signals of efficacy in treatment-refractory solid tumours. In a Phase II trial, 27 patients with advanced biliary tract cancers (BTC) were randomised 1:1 to CAP7.1 plus best supportive care (BSC), or BSC alone, with crossover to CAP7.1 upon disease progression. The primary objective was disease control rate (DCR) following 28-day cycles of CAP7.1 (200/150 mg/m²; iv), or BSC until progression. Secondary objectives included progression-free survival (PFS), time-to-treatment failure (TTF), overall survival (OS) and safety. Fourteen patients received CAP7.1 and 13 BSC. DCR favoured CAP7.1 vs. BSC (50% vs. 20%; treatment difference: 30%, 95%CI −18.44, 69.22, full analysis set [FAS]), with disease progression in 40% vs. 70%, respectively. Significantly longer median PFS was achieved for CAP7.1 vs. BSC: 66 vs. 39 days, respectively (hazard ratio [HR] 0.31; 95%CI 0.11, 0.86; p = 0.009; FAS). Similar trends were observed for TTF and OS. CES2-positive patients had longer median PFS (158 vs. 56 days) and OS (228 vs. 82 days) vs. CES2-negative patients. Adverse events were predictable, dose-dependent and consistent with those previously observed with etoposide. These efficacy and safety findings in second-line BTC warrant further clinical investigation of CAP7.1. Full article

(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)

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12 pages, 1241 KiB

Open AccessArticle

Examination of Prognostic Factors Affecting Long-Term Survival of Patients with Stage 3/4 Gallbladder Cancer without Distant Metastasis

by Ryota Higuchi, Takehisa Yazawa, Shuichirou Uemura, Yutaro Matsunaga, Takehiro Ota, Tatsuo Araida, Toru Furukawa and Masakazu Yamamoto

Cancers 2020, 12(8), 2073; https://doi.org/10.3390/cancers12082073 - 27 Jul 2020

Cited by 9 | Viewed by 2945

Abstract

In advanced gallbladder cancer (GBC) radical resection, if multiple prognostic factors are present, the outcome may be poor; however, the details remain unclear. To investigate the poor prognostic factors affecting long-term surgical outcome, we examined 157 cases of resected stage 3/4 GBC without distant metastasis between 1985 and 2017. Poor prognostic factors for overall survival and treatment outcomes of a number of predictable preoperative poor prognostic factors were evaluated. The surgical mortality was 4.5%. In multivariate analysis, blood loss, poor histology, liver invasion, and ≥4 regional lymph node metastases (LNMs) were independent prognostic factors for poor surgical outcomes; invasion of the left margin or the entire area of the hepatoduodenal ligament and a Clavien–Dindo classification ≥3 were marginal factors. The analysis identified outcomes of patients with factors that could be predicted preoperatively, such as liver invasion ≥5 mm, invasion of the left margin or the entire area of the hepatoduodenal ligament, and ≥4 regional LNMs. Thus, the five-year overall survival was 54% for zero factors, 34% for one factor, and 4% for two factors (p < 0.05). A poor surgical outcome was likely when two or more factors were predicted preoperatively; therefore, new treatment strategies are required for such patients. Full article

(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)

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10 pages, 1209 KiB

Open AccessArticle

Treatment of Patients with Advanced Biliary Tract Cancer with Either Oxaliplatin, Gemcitabine, and Capecitabine or Cisplatin and Gemcitabine—A Randomized Phase II Trial

by Alice Markussen, Lars Henrik Jensen, Laura Vittrup Diness and Finn Ole Larsen

Cancers 2020, 12(7), 1975; https://doi.org/10.3390/cancers12071975 - 20 Jul 2020

Cited by 16 | Viewed by 2323

Abstract

This study is an investigator-initiated randomized phase II trial focusing on the treatment of advanced biliary tract cancer with either oxaliplatin 50 mg/m² and gemcitabine 1000 mg/m² on day 1 in a two-week cycle with capecitabine 650 mg/m² twice-daily continuously or cisplatin 25 mg/m² and gemcitabine 1000 mg/m² on day 1 and day 8 in a three-week cycle. One-hundred patients were included. Forty-seven patients received oxaliplatin, gemcitabine, and capecitabine with a median progression-free survival (mPFS) of 5.7 months (95% CI 3.0–7.8) and a median overall survival (mOS) of 8.7 months (95% CI 6.5–11.2). Forty-nine patients received cisplatin and gemcitabine with a mPFS of 7.3 months (95% CI 6.0–8.7) and a mOS of 12.0 months (95% CI 8.3–16.7). This trial confirms a mOS of 12 months with cisplatin and gemcitabine, as found in earlier trials. With a superior tumor control rate of 79% vs. 60% (p = 0.045), a difference in the mPFS of 1.6 months (HR = 0.721, p = 0.1), and a difference in the mOS of 3.3 months (HR = 0.731, p = 0.1), cisplatin and gemcitabine should still be considered the standard first-line treatment for advanced biliary tract cancer. Full article

(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)

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Review

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21 pages, 2110 KiB

Open AccessReview

Translating Biomarkers of Cholangiocarcinoma for Theranosis: A Systematic Review

by Imeshi Wijetunga, Laura E. McVeigh, Antonia Charalambous, Agne Antanaviciute, Ian M. Carr, Amit Nair, K. Raj Prasad, Nicola Ingram and P. Louise Coletta

Cancers 2020, 12(10), 2817; https://doi.org/10.3390/cancers12102817 - 30 Sep 2020

Cited by 4 | Viewed by 2609

Abstract

Cholangiocarcinoma (CCA) is a rare disease with poor outcomes and limited research efforts into novel treatment options. A systematic review of CCA biomarkers was undertaken to identify promising biomarkers that may be used for theranosis (therapy and diagnosis). MEDLINE/EMBASE databases (1996–2019) were systematically searched using two strategies to identify biomarker studies of CCA. The PANTHER Go-Slim classification system and STRING network version 11.0 were used to interrogate the identified biomarkers. The TArget Selection Criteria for Theranosis (TASC-T) score was used to rank identified proteins as potential targetable biomarkers for theranosis. The following proteins scored the highest, CA9, CLDN18, TNC, MMP9, and EGFR, and they were evaluated in detail. None of these biomarkers had high sensitivity or specificity for CCA but have potential for theranosis. This review is unique in that it describes the process of selecting suitable markers for theranosis, which is also applicable to other diseases. This has highlighted existing validated markers of CCA that can be used for active tumor targeting for the future development of targeted theranostic delivery systems. It also emphasizes the relevance of bioinformatics in aiding the search for validated biomarkers that could be repurposed for theranosis. Full article

(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)

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12 pages, 464 KiB

Open AccessReview

Recent Progress in the Systemic Treatment of Advanced/Metastatic Cholangiocarcinoma

by Raluca Maria Fostea, Elisa Fontana, Gonzalo Torga and Hendrik-Tobias Arkenau

Cancers 2020, 12(9), 2599; https://doi.org/10.3390/cancers12092599 - 11 Sep 2020

Cited by 33 | Viewed by 3561

Abstract

Cholangiocarcinomas (CCAs) comprise of a heterogeneous group of cancers arising in the biliary tract (intrahepatic or iCCA, perihilar or pCCA and distal or dCCA; the latter are known under the collective term of eCCA), each subtype having its own particularities in carcinogenesis, management and prognosis. The increasing incidence in recent decades, limited treatment options and high mortality rates, even in the early stages, have led to an imperious need for more in-depth understanding and development of tailored treatments for this type of aggressive tumour. The wide use of molecular profiling has increased the understanding of biology and identified key molecular drivers, for example, IDH1 mutations or FGFR2 fusions for iCCA, or BRAF mutations in eCCA. Most recently, the FDA approved pemigatinib, an FGFR inhibitor and ivosidenib, an IDH1 inhibitor, but even though progress has been made to better understand the mechanisms of tumorigenesis, genetic make-up, and tumour resistance to standard chemotherapy and targeted therapies, cholangiocarcinomas still represent an important challenge in the daily clinical practice of oncology. The purpose of this review is to highlight the recent progress in the systemic treatment of advanced/metastatic CCAs with a focus on targeted drugs and their biomarkers currently evaluated in early-phase clinical trials. Full article

(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)

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26 pages, 1348 KiB

Open AccessReview

Role of Chemokines in the Biology of Cholangiocarcinoma

by Alessandra Caligiuri, Mirella Pastore, Giulia Lori, Chiara Raggi, Giovanni Di Maira, Fabio Marra and Alessandra Gentilini

Cancers 2020, 12(8), 2215; https://doi.org/10.3390/cancers12082215 - 07 Aug 2020

Cited by 12 | Viewed by 3197

Abstract

Cholangiocarcinoma (CCA), a heterogeneous tumor with poor prognosis, can arise at any level in the biliary tree. It may derive from epithelial cells in the biliary tracts and peribiliary glands and possibly from progenitor cells or even hepatocytes. Several risk factors are responsible for CCA onset, however an inflammatory milieu nearby the biliary tree represents the most common condition favoring CCA development. Chemokines play a key role in driving the immunological response upon liver injury and may sustain tumor initiation and development. Chemokine receptor-dependent pathways influence the interplay among various cellular components, resulting in remodeling of the hepatic microenvironment towards a pro-inflammatory, pro-fibrogenic, pro-angiogenic and pre-neoplastic setting. Moreover, once tumor develops, chemokine signaling may influence its progression. Here we review the role of chemokines in the regulation of CCA development and progression, and the modulation of angiogenesis, metastasis and immune control. The potential role of chemokines and their receptors as possible biomarkers and/or therapeutic targets for hepatobiliary cancer is also discussed. Full article

(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)

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19 pages, 1405 KiB

Open AccessReview

Molecular and Immunological Characterization of Biliary Tract Cancers: A Paradigm Shift Towards a Personalized Medicine

by Ines Malenica, Matteo Donadon and Ana Lleo

Cancers 2020, 12(8), 2190; https://doi.org/10.3390/cancers12082190 - 06 Aug 2020

Cited by 34 | Viewed by 4494

Abstract

Biliary tract cancers (BTCs) are a group of rare cancers that account for up to 3–5% of cancer patients worldwide. BTCs include cholangiocarcinoma (CCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). They are frequently diagnosed at an advanced stage when the disease is often found disseminated. A late diagnosis highly compromises surgery, the only potentially curative option. Current treatment regimens include a combination of chemotherapeutic drugs gemcitabine with cisplatin that have a limited efficiency since more than 50% of patients relapse in the first year. More recently, an inhibitor of fibroblast growth factor receptor 2 (FGFR2) was approved as a second-line treatment, based on the promising results from the NCT02924376 clinical trial. However, novel secondary treatment options are urgently needed. Recent molecular characterization of CCA and GBC highlighted the molecular heterogeneity, etiology, and epidemiology in BTC development and lead to the classification of the extrahepatic CCA into four types: metabolic, proliferating, mesenchymal, and immune type. Differences in the immune infiltration and tumor microenvironment (TME) have been described as well, showing that only a small subset of BTCs could be classified as an immune “hot” and targeted with the immunotherapeutic drugs. This recent evidence has opened a way to new clinical trials for BTCs, and new drug approvals are highly expected by the medical community. Full article

(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)

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21 pages, 585 KiB

Open AccessEditor’s ChoiceReview

Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm

by Sakti Chakrabarti, Mandana Kamgar and Amit Mahipal

Cancers 2020, 12(8), 2039; https://doi.org/10.3390/cancers12082039 - 24 Jul 2020

Cited by 51 | Viewed by 4684

Abstract

Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC. Full article

(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)

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Other

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9 pages, 1126 KiB

Open AccessCommentary

Selected Patients with Unresectable Perihilar Cholangiocarcinoma (pCCA) Derive Long-Term Benefit from Liver Transplantation

by Adiba I. Azad, Charles B. Rosen, Timucin Taner, Julie K. Heimbach and Gregory J. Gores

Cancers 2020, 12(11), 3157; https://doi.org/10.3390/cancers12113157 - 27 Oct 2020

Cited by 16 | Viewed by 2696

Abstract

Selected patients with unresectable perihilar cholangiocarcinoma (pCCA) derive long-term benefits from liver transplantation. Between 1993–2019, our group at Mayo Clinic performed 237 transplants for pCCA. With this experience, we note that two distinct patient populations comprise this group of pCCA patients: those with underlying primary sclerosing cholangitis (PSC) and those without identifiable risk factors termed sporadic or de novo pCCA. Long-term survival after transplant is better in PSC patients (74% five-year survival) than in those with de novo pCCA (58% five-year survival). Herein, we review the likely clinical factors contributing to the divergence in outcomes for these two patient populations. We also offer our insights on how further advances may improve patient selection and survival, focusing on the de novo pCCA patient population. Full article

(This article belongs to the Special Issue Research Progress of Biliary Tract Cancers)

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