Updates on the Understanding of Cholangiocarcinoma
On October 17 and 18, 2019, a group of international experts convened in Phoenix, AZ, for the First Annual Cholangiocarcinoma Summit. The goal of the meeting was to discuss the latest clinical data on the disease, as well as the implications of these findings for providers and patients. Each topic included in the summit was presented by 2 speakers and then analyzed by a chorus of experts in the field. This format was chosen to provide a consensus, whenever possible, on each topic that was presented.
This publication provides highlights of key presentations and discussions from the meeting. In this first article, we discuss the epidemiology of cholangiocarcinoma (CCA), the role of aspirin and statins as chemoprevention, the molecular and genetic pathogenesis of the disease, treatment strategies, urgent clinical needs, and the latest hot topics.
Epidemiology of Cholangiocarcinoma
CCA, also known as bile duct cancer, is a rare malignancy that is diagnosed in approximately 8000 individuals in the United States each year.1 The peak age at presentation is in the seventh decade of life.2 The intrahepatic form of CCA is the second most common primary liver tumor after hepatocellular carcinoma (HCC).
The epicenter of CCA is Thailand and nearby regions, where the most common predisposing cause is believed to be liver fluke infection. In contrast, in the Western world, the most common predisposing cause of the disease is primary sclerosing cholangitis (PSC).3 The global variation in incidence not only reflects differences in genetic factors, but also the “exposome,” which has been defined as the collection of environmental factors to which one has been exposed over his or her lifetime.4
The incidence of intrahepatic CCA worldwide has been increasing, a pattern that began decades ago, whereas the incidence of extrahepatic CCA has remained stable or has been on the decline. Overall, the incidence of CCA is on the rise. The reported trends in CCA incidence should be interpreted with caution, however, because current coding systems do not consider the accurate recording of CCA data and thus may contribute to the reported rise in intrahepatic CCA.
International consistency and accuracy in the topographic classification of CCA are needed to allow accurate monitoring of disease rates. The belief is that bile duct cancers should be subclassified as intrahepatic, perihilar, or distal,5 and that International Classification of Diseases, 11th Revision,6 and subsequent iterations of International Classification of Diseases for Oncology should have separate topography and morphology codes for each of these 3 cancer subtypes.7 To improve the collection of data, healthcare professionals must ensure that the correct code is recorded at tumor boards, in clinical case notes, and on death certificates, and that administrative teams are appropriately trained in the assignment of codes.
Regardless of the way in which CCA is classified, its incidence appears to be increasing, thus warranting more studies regarding the cause of the disease, as well as more effective therapies.
Aspirin and Statins as Chemoprevention
Given the known anti-inflammatory effects of aspirin and statins, investigators have studied the potential role of these agents in the prevention of biliary tract cancers. A hospital-based, case-control study demonstrated that aspirin use was significantly associated with a 2.7-fold to 3.6-fold decreased risk for the 3 subtypes of CCA.8
Findings from a population-based cohort study derived from 3 Swedish registries suggest that the use of low-dose aspirin and statins decreases the risk for biliary tract cancer in a subtype- and sex-dependent manner.9 The investigators in this study reported that among women, a nonsignificant decrease in the risk for extrahepatic CCA was observed with aspirin use alone. Furthermore, statin use alone significantly reduced the risk for extrahepatic CCA in women by 40% and in men by 53%. Moreover, women who were exposed to aspirin alone, a statin alone, or both had a 24% to 28% reduction in the risk for gallbladder cancer. Among men, although the estimates did not reach statistical significance, the estimates for use of a statin alone and the combined use of low-dose aspirin and a statin suggested protection against gallbladder cancer.9
A meta-analysis of 4 case-control studies and 1 retrospective cohort study showed that aspirin users are less likely to develop CCA compared with aspirin nonusers (odds ratio, 0.56).10 The definition of aspirin use in each study differed, however, with only 1 study considering an individual with a duration of use of ≥6 months to be an aspirin user. Although these studies suggest a favorable chemopreventive effect of aspirin, it cannot be concluded that aspirin reduces the risk for CCA.
Studies have demonstrated no consistent effect of statin use on the development of CCA. This finding is supported by a meta-analysis of 27 randomized controlled trials that failed to show an association between statin use for >2 years and the risk for several types of cancers.11
The lack of rigor in describing biliary tract cancers was recognized by the chorus of experts. In addition to the 3 distinct topographic and morphologic forms of CCA, biliary tract cancers comprise gallbladder cancer and ampullary cancer, all of which behave differently. Distinguishing among these various forms of biliary tract cancer is important when interpreting the results of clinical trials.
A member of the chorus noted the difficulty involved in discriminating between ampullary cancer and extrahepatic CCA, indicating that approximately 5% of patients enrolled in the Advanced Biliary Tract Cancer (ABC)-02 trial12 had ampullary cancer that had been misdiagnosed as biliary tract cancer. The International Rare Cancers Initiative is assessing the biology of rare cancers (<2/100,000), such as cancer of the ampulla of Vater, to facilitate the development of international clinical trials for these malignancies. “Only in that way can you distinguish between a ductile pancreatic cancer, a bile duct cancer, and a small bowel cancer,” said one of the chorus members.
In addition, HCC is often present at the diagnosis of carcinoma of unknown primary origin. According to one of the chorus members, ≤10% of HCC tumors are combined HCC and CCA, which may have been overlooked because of a historical reluctance to biopsy HCC. Many cases of CCA are treated as local disease at nonspecialized centers. A movement is underway in the United Kingdom to have every diagnosed case of CCA reviewed at a regionally recognized hepatobiliary center that has appropriate expertise in oncology, radiology, and surgery.
In terms of chemoprevention, one chorus member requested a randomized controlled trial of aspirin versus placebo in patients with PSC, because the ability to demonstrate a benefit from prophylactic therapy is often greater in populations at higher risk. The consensus was that the risk for CCA in a patient with PSC is 0.5% to 1.0% per year, with a lifetime risk of ≤20%.
Molecular and Genetic Pathogenesis of Cholangiocarcinoma
Inflammation and immune response pathways are involved in the pathogenesis of CCA. Whereas obesity is recognized as a significant risk factor for HCC, its contribution to the risk for CCA is underrecognized. In case-control studies, excess weight or obesity in early adulthood is associated with an increased risk for intrahepatic CCA, particularly among women, compared with normal-weight individuals. Obesity is also negatively correlated with the age of onset of intrahepatic CCA.
Chronic inflammation plays an important role in the relationship between obesity and cancer. Genes involved in the inflammatory pathway are candidate genes for susceptibility to cancer. Those genes in the inflammatory pathway that are linked to the development of CCA include COX-2 and WRAP53.
Genetic variations in lipid metabolism pathways may also predispose individuals to the risk for CCA, as the prevalence of G alleles of PNPLA3 among patients with CCA is similar to that observed in patients with HCC.
Molecular profiling of nonfluke-related intrahepatic CCA reveals that mutations in IDH1/2, BAP1, and PBRM1 are more common in Western countries than in Asian regions. Conversely, mutations in TP53 are found more frequently in Asian regions.
Mutations in IDH1/2 and BAP1 are prevalent regardless of CCA subtype, whereas mutations in fibroblast growth factor receptor 2 (FGFR2) are more common in intrahepatic CCA versus perihilar and extrahepatic CCA. In addition, mutations in SMAD4, TP53, and KRAS are observed more frequently in perihilar and extrahepatic CCA. Few sequencing studies have been conducted in patients with fluke-positive CCA, but available data show that mutations in TP53 are highly prevalent (Figure 1).
In addition to genetic mutations, focal copy number aberrations, such as deletion of CDKN2A and amplification of cyclin D1, have also been found in patients with CCA and are associated with expected changes in gene expression. The dysregulation of CDKN2A commonly found in patients with CCA suggests a targetable pathway, perhaps through CDK4/6 inhibition.
Mixed and combined intrahepatic CCA/HCC was recently found to have monoclonal origins. Cancer-specific mutations can exist in both intrahepatic CCA and HCC regions (ie, IDH1 and CTNNB1) of the same tumor sample.13
The genomics suggest that CCA is pharmacologically actionable, but additional research is warranted to reveal novel vulnerabilities.
Treatment Strategies for Cholangiocarcinoma
The rationale for biliary drainage in CCA is to relieve obstructive symptoms, minimize obstruction of the future liver remnant (FLR) for resection candidates, reduce the risk for postoperative liver failure, and relieve cholestasis, which may increase hepatic toxicity and impair postoperative liver regeneration.
Several techniques are available for achieving biliary drainage in patients with CCA. Endoscopic retrograde cholangiopancreatography (ERCP) with dual stenting (usually plastic) is the standard drainage technique for patients with hilar CCA. Endoscopic ultrasound (EUS)-guided intrahepatic biliary drainage of the left lateral lobe can be considered in patients who are not good candidates for percutaneous drainage. EUS-guided drainage can be combined with ERCP stenting.
Endoscopic biliary drainage is preferable to percutaneous drainage, because of the relatively high recurrence rate of CCA in percutaneous transhepatic biliary drainage fistulae.14 Percutaneous drains are avoided in patients with PSC who are candidates for transplant.
Surgical strategies for patients with CCA differ according to subtype. In patients with distal CCA, the surgery resembles a Whipple procedure, whereas those with intrahepatic CCA are managed with liver resection and those with hilar CCA are treated with liver resection plus bile duct resection. All these surgical procedures should include portal lymphadenectomy and selective distant nodal sampling.
A study showed that among patients with perihilar CCA who underwent liver resection, an FLR volume of <30% predicted higher rates of postoperative mortality compared with higher FLR volumes. Complete preoperative biliary drainage improved 90-day mortality in patients with intermediate (30%-50%) FLR volume compared with those with incomplete drainage. In contrast, no postoperative mortality was observed in undrained patients with FLR volumes of >50%.15 A separate study showed that preoperative cholangitis in the setting of an FLR volume of <30% increased the risk for hepatic insufficiency, liver failure, and death compared with no preoperative cholangitis (Figure 2).16
For patients with intrahepatic CCA, although surgery is extremely effective for local tumor control, it is curative in only a minority of individuals. Therefore, the development of more effective adjuvant treatments is critically important in this population. Among patients with hilar CCA or distal CCA, the pattern of spread tends to be locoregional, but the margins are almost always close, and an isolated nodal recurrence pattern is common.
In patients with intrahepatic CCA, mortality from primary tumors that are not resected results from the tumor causing portal venous and hepatic venous occlusions, as well as occlusions and obstructions of the biliary tree, leading to atrophy and eventual liver failure.17 In those with hilar CCA, relentless episodes of cholangitis, regardless of the use of effective nonoperative therapy, is the leading cause of death.16
In patients with unresectable liver disease, the use of local therapies is more critical if the tumor occludes the hepatic vein/inferior vena cava confluence and the portal vein and biliary bifurcation. Ablative doses of external beam radiation therapy are more effective than palliative doses in extending survival in patients with unresectable biliary cancers. Patients who receive insufficient doses of localized radiation that lead, in turn, to poor local tumor control typically die from liver failure related to the primary tumor.
What Are the Most Urgent Clinical Needs in Cholangiocarcinoma?
Patients with CCA have identified several urgent clinical needs, including earlier and improved diagnostics, more specialists, and timely results following scans. They also want better access to resources immediately following diagnosis; these resources should explain CCA and its treatments, as well as how to participate in clinical trials.
A survey of >1000 patients with CCA revealed that 30% would be willing to undergo surgery or transplantation even if the risks for complications, including death, were high. Half of the patients surveyed indicated that they would undergo surgery if it increased their likelihood of survival to ≥2 years, and approximately 20% said that they would undergo surgery if it improved their chance of surviving 3 to 12 months. Furthermore, 50% of patients reported that they would be willing to undergo surgery even if there was no chance for a cure.18
Patients also want access to experts for second opinions related to early molecular profiling, clinical trials, and treatments. In the above-mentioned survey, >90% of patients viewed molecular profiling as an important, necessary part of their treatment plan. Patients also indicated that they wanted a healthcare provider who thinks outside the box, views each patient as an individual, is willing to tailor a treatment plan to them, and would take risks with their treatment plan. Nearly 80% of patients reported that they would be willing to try a treatment even if there was no guarantee of it helping them, and 85% said that they would enter a clinical trial that had a high risk but the potential for improved outcomes.18
Nurses have identified the need for consistency regarding discharge instructions, as well as better instructions for patients receiving biliary stents and drains. Patient quality of life is negatively affected by a lack of adequate knowledge regarding the care of stents and external biliary drains, with the latter being complex and requiring frequent maintenance.19
The Nursing Advisory Board of The Cholangiocarcinoma Foundation gathered discharge instructions on biliary drains at baseline from 10 university centers and developed a SurveyMonkey questionnaire based on this information.19 The questionnaire was sent to the 27 leading cancer centers of the National Comprehensive Cancer Network.
Of the 26 centers that responded, 23 completed the entire survey. Results showed that at least 74% of the time, patient education was completed by a combination of registered nurses and nurse practitioners. Verbal and written instructions were provided by 87% of the cancer centers; 13% provided verbal instructions only.
These findings suggest that patient education is inconsistent with respect to all the questions asked. There were wide variations regarding the care of external biliary drains, and less variation regarding internal stent exchange. At least 95% of the cancer centers instructed patients on signs and symptoms they need to report (ie, fever, jaundice, chills, absence of drainage, nausea, and vomiting); these instructions were given predominantly by radiology nurses.
According to physicians, the most urgent need is the encouragement of clinical trial participation, which requires collaboration and patient advocacy to increase awareness, along with supportive care to convince patients to stay on study and to ensure that their needs are met. They expressed that the second most urgent need is routine tumor profiling, which can enhance the understanding of tumor heterogeneity, resistance, and sequencing and combinations of therapies.
They also identified innovation as another critical need. In the diagnosis of CCA, brushing is inadequate and results in delayed care. Fluorescence in situ hybridization and early use of liquid biopsy may hasten appropriate patient care. Proper sequencing of therapies also requires innovation. This was the case with chronic myeloid leukemia, which previously had dim prospects for survival but has now become a chronic disease because of the use of targeted therapies.
Physicians believe that big data and smart data are additional pressing needs for enhancing the treatment of rare cancers such as CCA. Komodo Health, for example, has an outcomes database that lets healthcare providers know where patients are receiving treatment, their access to therapies, and their treating clinicians.20 Further development of artificial intelligence will allow for the identification of patterns that predict recurrence and response to treatment.
The chorus of experts agreed that CCA incidence rates do not appear to be plateauing, which is alarming. Data suggest that the increasing rates of intrahepatic CCA may be related to concomitant increases in the prevalence of certain risk factors, such as cirrhosis, alcoholic liver disease, and hepatitis C virus infection. They noted that a specific risk factor for most patients with CCA, however, has yet to be identified.
One of the less commonly described modifiable risk factors for CCA is metabolic syndrome. Case-control and cohort studies show a correlation between body mass index and the risk for CCA, particularly intrahepatic CCA.21,22
The data reviewed at the summit showed that obese patients are developing intrahepatic CCA at a younger age, with onset 5 to 10 years earlier than nonobese patients. A much larger percentage of intrahepatic CCA cases than previously thought may be attributed to obesity. “I think this is an area in which we really need to pay a lot of attention, particularly given the increase in obesity rates, at least in North America,” said one of the experts. Overall, the data presented highlight the interplay between genetic factors and the environment.
The audience was polled with respect to the question, “Where should the research focus be for the role of obesity in CCA?” More than one-third (38%) responded, “educational interventions for obese patients and their providers,” whereas 26% answered “predictive biomarkers in obese patients” and 24% responded “risk reduction strategies in obese patients.” A minority (12%) of the participants believed that CCA screening programs in obese patients should be the focus.
The role of systemic therapy in CCA continues to evolve in advanced biliary tract cancers, as does the treatment paradigm in general. Although the ABC-02 trial set the benchmark for a standard of care in this setting, no single chemotherapeutic agent or combination regimen thus far has consistently led to objective tumor shrinkage, forestalled the need for palliative interventions, or extended survival beyond approximately 1 year. The overall response rate in the ABC-02 trial was only 30% collectively.23 Most participants were in favor of clinical trial enrollment in the CCA patient population, whenever possible.
Next-generation sequencing (NGS) is a wave of the future, given the multiple molecular alterations that have been characterized in patients with CCA. These molecular alterations can be targeted by specific inhibitors that have already been developed and are continuing to be developed.
The discussion on urgent clinical needs in CCA highlighted the fact that patients are already at the forefront of change by requesting more specialists, more education, and more aggressive, novel treatment approaches—even at the cost of high mortality and even if the likelihood of cure is remote. Patients are requesting more routine insurance coverage for innovative diagnostic and therapeutic techniques, routine access to molecular profiling, and routine participation in clinical trials, even if there is no guarantee that an investigational treatment will help and if high risks are involved.
It was agreed that biliary drainage is an important part of patient care, both in the palliative and therapeutic settings. Regarding biliary drainage, the audience was asked to consider the following case study:
A 61-year-old patient with a type 3A hilar CCA presents to the clinic. Symptoms include jaundice and mild pruritus, but the patient is otherwise well and is afebrile. The patient’s body mass index is 36, and there is radiographic evidence of a fatty liver. Laboratory values are as follows: bilirubin, 5.4 mg/dL; alkaline phosphatase, 304 U/L; aspartate aminotransferase/alanine aminotransferase, 200s (U/L); white blood cell (WBC) count, 13.4 x 109/L. Which of these factors would lead you to opt for biliary drainage?
Almost half (48%) of the audience members responded that jaundice and pruritus would lead them to opt for biliary drainage, whereas 26% selected the bilirubin level. Overall, 17% of the participants indicated that the patient would require portal vein embolization to ensure adequate FLR volume. Additionally, 9% of the participants responded that the WBC count would matter most.
According to multiple chorus experts, the decision to stent may depend on whether the cancer is resectable. “If it’s resectable, you want to do biliary decompression, but you are also going to need to do portal vein embolization,” noted one expert. “However, if it is not resectable and the treatment is going to be chemotherapy…I do not think any oncologist will give chemotherapy with a bilirubin of 5.4 mg/dL. That is when the bilirubin in the context of other variables may also have an important effect on that decision.”
Updates on Cholangiocarcinoma in 2019: What’s Hot?
Milind Javle, MD, Professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, provided an update on the latest findings in CCA. According to Dr Javle, ultrasound screening and early detection of CCA are possible in an endemic population. In a 5-year population-based study of 4225 Taiwanese adults aged 30 to 60 years, CCA was detected in 32 individuals, with 21 of the 32 cases resectable.24 Two simple radiologic metrics—periductal fibrosis and biliary ductal dilation—correlated well with each other and with CCA.
These data suggest that preneoplastic lesions are detectable and may have implications for screening high-risk groups in Western populations, specifically those patients who have nonalcoholic steatohepatitis or PSC.
A transformation in the management of CCA has occurred with the advent of NGS and targeted therapeutics. “CCA is a model for precision medicine and oncology,” noted Dr Javle.
A distinct pattern of mutations is observed in patients with intrahepatic CCA, with a predominance of isocitrate dehydrogenase (IDH), FGFR, and BRAF mutations.25 Extrahepatic CCA has a high frequency of ERBB2 mutations, as well as some BRAF, EHCCA, and KRAS mutations, whereas gallbladder cancer has a high frequency of ERBB2 amplification.26
Unfortunately, only 50% to 60% of patients with intrahepatic CCA and <30% of patients with extrahepatic CCA have enough DNA extracted from tumor tissue for sequencing. The molecular landscape of CCA is accessible via circulating tumor DNA, which can be used to personalize treatment.
In clinical trials, patients with CCA containing FGFR2 fusions had superior response rates to FGFR inhibitors than to chemotherapy in the second-line setting. A relatively small percentage of patients do not respond to FGFR inhibitors in the presence of FGFR fusions. The small-molecule tyrosine kinase inhibitors directed against FGFR fusions that are in development all induce a similar disease control rate (approximately 80%) with a similar progression-free survival (PFS) of approximately 6 months (Table).27-31 In patients with CCA who have received 1 prior line of chemotherapy, the response rate to FGFR inhibitors seems to be higher compared with patients who have received ≥2 prior lines of chemotherapy.27
According to Dr Javle, “It is therefore imperative upon all of us that we investigate these agents earlier in the disease course, such as in first-line therapy, where response rates may be perhaps even higher.”
The most common mechanism of resistance to FGFR inhibition was gatekeeper mutations in the adenosine triphosphate binding pocket.32 Several secondary gatekeeper mutations can be detected both in the blood and in the tumor. These tumors can then be targeted by irreversible pan-FGFR inhibitors.
Recent results from the phase 3 ClarIDHy study showed the IDH1 inhibitor ivosidenib to be effective in patients with IDH1-mutant intrahepatic CCA—a mutation that occurs in approximately 15% of individuals with CCA.33 Although to date, personalized therapy has focused on mutational targeting, much information exists beyond the mutations, including data on RNA and organoids.
Trials of the immunotherapeutic agent pembrolizumab with or without granulocyte-macrophage colony-stimulating factor in patients with advanced biliary tract cancer have reported modest response rates.34 Therefore, the use of standard single-agent checkpoint inhibitor therapy may not be the ideal solution for patients with this disease, who may instead require combination regimens.
Until recently, no standard adjuvant therapy had been available for the treatment of patients with CCA. The BILCAP adjuvant therapy trial demonstrated numerical superiority of adjuvant capecitabine versus observation, although it did not reach statistical significance.35 A protocol-specified sensitivity analysis, adjusting for relevant prognostic factors, showed a significant approximately 30% improvement in overall survival with adjuvant capecitabine, which has become the standard of care following surgical resection.35
The use of ablative radiotherapy has not been evaluated in randomized phase 3 studies. Instead, large-volume institutions and real-world studies serve as the basis of information on the utilization of this treatment. If the underlying liver function in a patient with intrahepatic or extrahepatic CCA is good, then the liver can withstand large doses of radiation. In a retrospective, dose-response analysis of 79 patients with inoperable intrahepatic CCA who received radiation doses of 35 to 100 Gy (median biologic equivalent dose, 80.5 Gy), PFS and overall survival reached a plateau with a median follow-up of 33 months, indicating that a subgroup of patients benefit from radiation following systemic chemotherapy.17
Recent advances in the treatment of CCA are explored in greater detail in subsequent articles in this publication.
- American Cancer Society. Key statistics for bile duct cancer. www.cancer.org/cancer/bile-duct-cancer/about/key-statistics.html. Accessed December 11, 2019.
- Alsaleh M, Leftley Z, Barbera TA, et al. Cholangiocarcinoma: a guide for the nonspecialist. Int J Gen Med. 2018;12:13-23.
- Prueksapanich P, Piyachaturawat P, Aumpansub P, et al. Liver fluke-associated biliary tract cancer. Gut Liver. 2018;12:236-245.
- DeBord DG, Carreón T, Lentz TJ, et al. Use of the “exposome” in the practice of epidemiology: a primer onomic technologies. Am J Epidemiol. 2016;184:302-314.
- Waseem D, Tushar P. Intrahepatic, perihilar and distal cholangiocarcinoma: management and outcomes. Ann Hepatol. 2017;16:133-139.
- World Health Organization (WHO). WHO releases new International Classification of Diseases (ICD-11). www.who.int/news-room/detail/18-06-2018-who-releases-new-international-classification-of-diseases-(icd-11). Accessed November 26, 2019.
- Khan SA, Genus T, Morement H, et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol. 2019;71:1261-1262.
- Choi J, Ghoz HM, Peeraphatdit T, et al. Aspirin use and the risk of cholangiocarcinoma. Hepatology. 2016;64:785-796.
- Marcano Bonilla L, Schleck C, Harmsen W, et al. Associations of aspirin, non-aspirin NSAIDs, statins, and metformin with risk of biliary cancer: a Swedish population-based cohort study. J Clin Transl Sci. 2019;3(suppl 1):35. Abstract 3437.
- Lapumnuaypol K, Tiu A, Thongprayoon C, et al. Effects of aspirin and non-steroidal anti-inflammatory drugs on the risk of cholangiocarcinoma: a meta-analysis. QJM. 2019;112:421-427.
- Cholesterol Treatment Trialists’ (CTT) Collaboration; Emberson JR, Kearney PM, Blackwell L, et al. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One. 2012;7:e29849. doi: 10.1371/journal.pone.0029849.
- Valle J, Wasan H, Palmer DH; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273-1281.
- Xue R, Chen L, Zhang C, et al. Genomic and transcriptomic profiling of combined hepatocellular and intrahepatic cholangiocarcinoma reveals distinct molecular subtypes. Cancer Cell. 2019;35:932-947.
- Takahashi Y, Nagino M, Nishio H, et al. Percutaneous transhepatic biliary drainage catheter tract recurrence in cholangiocarcinoma. Br J Surg. 2010;97:1860-1866.
- Wiggers JM, Groot Koerkamp B, Cieslak KP, et al. Postoperative mortality after liver resection for perihilar cholangiocarcinoma: development of a risk score and importance of biliary drainage of the future liver remnant. J Am Coll Surg. 2016;223:321-331.e1.
- Ribero D, Zimmitti G, Aloia TA, et al. Preoperative cholangitis and future liver remnant volume determine the risk of liver failure in patients undergoing resection for hilar cholangiocarcinoma. J Am Coll Surg. 2016;223:87-89.
- Tao R, Krishnan S, Bhosale PR, et al. Ablative radiotherapy does lead to a substantial prolongation of survival in patients with inoperable intrahepatic cholangiocarcinoma: a retrospective dose response analysis. J Clin Oncol. 2016;34:219-226.
- Bachini M, Moravek C, Lindsey SC, et al. The patient perspective to cancer care: aligning physician expectations with patients’ wishes. HPB. 2019;21:S220.
- Driskill K, Pratt M, Drapek LIyer R, et al. Nursing care and education for patients with biliary stents and drains: an on-going multi-center quality improvement project. Poster presented at: Oncology Nursing Society’s Annual Conference 2018; May 17-20, 2018; Washington, DC. Poster 84. https://epostersonline.com/ons2018/node/418. Accessed December 3, 2019.
- Komodo Health. www.komodohealth.com/solutions. Accessed December 3, 2019.
- Grainge MJ, West J, Solaymani-Dodaran M, et al. The antecedents of biliary cancer: a primary care case-control study in the United Kingdom. Br J Cancer. 2009;100:178-180.
- Oh SW, Yoon YS, Shin SA. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J Clin Oncol. 2005;23:4742-4754.
- Park JO, Oh DY, Hsu C, et al. Gemcitabine plus cisplatin for advanced biliary tract cancer: a systematic review. Cancer Res Treat. 2015;47:343-361.
- Sungkasubun P, Siripongsakun S, Akkarachinorate K, et al. Ultrasound screening for cholangiocarcinoma could detect premalignant lesions and early-stage diseases with survival benefits: a population-based prospective study of 4,225 subjects in an endemic area. BMC Cancer. 2016;16:346.
- Jiao Y, Pawlik TM, Anders RA, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet. 2013;45:1470-1473.
- Javle M, Bekaii-Saab T, Jain A, et al. Biliary cancer: utility of next-generation sequencing for clinical management. Cancer. 2016;122:3838-3847.
- Javle M, Kelley RK, Roychowdhury S, et al. A phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor (TKI), in patients with previously-treated advanced cholangiocarcinoma containing FGFR2 fusions. Poster presented at: European Society for Medical Oncology (ESMO) 2018; October 19-23, 2018; Munich, Germany. Poster LBA28.
- Hollebecque A, Borad M, Sahai V, et al. Interim results of FIGHT-202, a phase II, open-label, multicenter study of INCB054828 in patients (pts) with previously treated advanced/metastatic or surgically unresectable cholangiocarcinoma (CCA) with/without fibroblast growth factor (FGF)/FGF receptor (FGFR) genetic alterations. Ann Oncol. 2018;29(suppl 8):vii258. Abstract 756P. doi: 10.1093/annonc/mdy282.139.
- Goyal L, Arkenhau H-T, Tran B, et al. Early clinical efficacy of TAS-120, a covalently bound FGFR inhibitor in patients with cholangiocarcinoma. Abstract presented at: European Society for Medical Oncology (ESMO) 2017; September 8-12, 2017; Madrid, Spain. Ann Oncol. 2017;28(suppl 3):I45. Abstract O-020.
- Mazzaferro V, El-Rayes BF, Droz dit Busset M, et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019;120:165-171.
- Chen Y-Y, Park JO, Su W-C, et al. Preliminary results of a ph2a study to evaluate the clinical efficacy and safety of erdafitinib in Asian patients with biomarker-selected advanced cholangiocarcinoma (CCA). Ann Oncol. 2018;29(8):vii209. Abstract 624PD. doi: 10.1093/annonc/mdy282.008.
- Dai S, Zhou Z, Chen Z, Xu G, Chen Y. Fibroblast growth factor receptors (FGFRs): structures and small molecule inhibitors. Cells. 2019;8(6):614.
- Abou-Alfa GK, Macarulla Mercade T, Javle M, et al. ClarIDHy: a global, phase III, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Abstract presented at: European Society for Medical Oncology (ESMO) 2019; September 27-October 1, 2019; Barcelona, Spain. Ann Oncol. 2019;30(suppl 5):v872-v873. Abstract LBA10_PR.
- Ueno M, Chung HC, Nagrial A, et al. Pembrolizumab for advanced biliary adenocarcinoma: results from the multicohort, phase II KEYNOTE-158 study. Abstract presented at: European Society for Medical Oncology (ESMO) 2018; October 19-23, 2018; Munich, Germany. Ann Oncol. 2018;29(suppl 8):viii210. Abstract 625PD.
- Primrose JN, Fox RP, Palmer DH, et al; BILCAP study group. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019;20:663-673.