Cholangiocarcinoma is a family of relatively rare malignancies that occur in the epithelial cells of the biliary duct. Generally, they are characterized as somewhat aggressive, and anatomically, cholangiocarcinoma is subdivided, based upon the malignancy location, with intrahepatic or extrahepatic disease occurring in the biliary duct within or outside the liver, respectively.
Recently, Bassam Estfan, MD, from the Taussig Cancer Institute of the Cleveland Clinic Cancer Center, and colleagues authored a study which presented the epidemiologic trends for incidence and mortality in U.S.-based patients with cholangiocarcinoma who had received diagnoses between 2000 and 2015 based on SEER database (Clin Res Hepatol Gastroenterol 2020;44:885-893). Regarding patient care, Estfan stated, "The best way to manage patients with cholangiocarcinoma is through a multidisciplinary model with representation of multiple specialties."
Cholangiocarcinoma Statistics
Between 2000 and 2015, the authors identified 16,189 U.S.-based cases of cholangiocarcinoma, with nearly two-thirds of the cases (64.4%) being intrahepatic. Slightly more than half of these cases were in males (51.3%), and most patients were White (78.4%) and older than 65 years (63%). Incidence-based mortality analyses included 13,121 cholangiocarcinoma patients who died during the study period.
During the study period, the overall incidence of cholangiocarcinoma was 11.977 cases per million person-years (95% CI: 11.792-12.164). Their analyses revealed a high incidence rate of 13.942 cases per million person-years in males (95% CI: 13.638-14.251), while in patients older than 65 years, a figure of 63.434 cases per million person-years (95% CI: 62.205-64.683) was obtained. In Asians, the incidence was 17.776 cases per million person-years (95% CI: 17.004-18.577).
Between 2000 and 2015, significant increases were noted in the overall incidence rates of cholangiocarcinoma, with an annual percent change of 5.063 percent (95% CI: 4.717-5.410%, P < 0.001). Most subgroup analyses revealed similar trends in several subgroups, with significant increases in incidence rates being noted over the course of the study period. Increases were observed in all disease stages.
From 2000 to 2015, the overall incidence-based mortality of cholangiocarcinoma was 10.295 cases per million person-years (95% CI: 10.118-10.474). As with the incidence rates, high incidence-based mortality rates for cholangiocarcinoma were observed in males, with a figure of 12.160 cases per million person-years (95% CI: 11.866-12.460) and in the elderly (patients older than 65 years), where a value of 57.852 cases per million person-years (95%CI: 56.646-59.077) was obtained. For Asians, the incidence-based mortality rate was high, at 14.962 cases per million person-years (95% CI: 14.246-15.706).
Between 2000 and 2013, the overall incidence-based mortality rates of cholangiocarcinoma increased at a rate of 5.964 percent per year (95% CI: 5.619-6.309%, P < 0.001). However, between 2013 and 2015, a significant decrease, -20.399 percent per year (95% CI: -25.029 to -15.483%, P < 0.001), was noted.
Both access to health care and treatment options are thought to be critical factors in patient outcomes for cholangiocarcinoma. In the United States, poorer outcomes have been noted for African-American or Hispanic patients who were diagnosed with intrahepatic cholangiocarcinoma. It is thought that these outcomes may be related to their limited access to health care. Since people of these ethnicities constitute some of the fastest-growing demographics in the U.S., it is thought that special care must be taken to reducing health care disparities in the treatment of cholangiocarcinoma.
Clinical Challenges
When discussing the intricacies of treating patients with cholangiocarcinoma, Estfan noted, "There are several challenges in the management of cholangiocarcinoma, and we can discuss several of them here. Cholangiocarcinoma, in its different subtypes, is a somewhat rare cancer and many providers may not be familiar with the surgical and oncological management of it. While its incidence is increasing with time, it is still an uncommon cancer type.
"The second challenge is presentation," he observed, noting that, "while extrahepatic cholangiocarcinoma may be diagnosed earlier due to biliary obstruction, it is not uncommon for intrahepatic cholangiocarcinoma to present at an advanced stage, given the lack of specific symptoms.
"The third challenge is diagnostic," Estfan stated. "We can cite a couple of examples; perihilar cholangiocarcinoma is often difficult to diagnose, even in the right clinical setting. With bile duct stenosis as the only finding sometimes, obtaining tissue confirmation can be challenging even with repeated endoscopic retrograde cholangiopancreatographies (ERCPs), and this may lead to delays in treatment. Another example is the mischaracterization of intrahepatic cholangiocarcinoma as a carcinoma or adenocarcinoma of unknown primary, which may lead to a different treatment path, one that is less specific or targeted.
"One last challenge is therapeutic," Estfan noted. "In its earlier stages, cholangiocarcinoma can be cured surgically, but this should be done at centers with high volume cases and expertise. Access to such centers (either tertiary or academic) is not everywhere; furthermore, in the advance setting, cholangiocarcinomas are not known to be highly responsive to chemotherapy."
Despite this shortcoming, "More strides have been made to understand the molecular subtypes, and as a result, the development of targeted treatments has shown promise."
Therapeutic Interventions
Describing the typical interventions used for patients with cholangiocarcinoma, Estfan noted, "Early-stage cholangiocarcinoma is best treated with surgical resection; the type of surgery depending on the location of the cancer along the biliary tract. For most, adjuvant chemotherapy (with capecitabine) is recommended afterwards."
For patients who have locally advanced or metastatic cholangiocarcinoma, "The mainstay of treatment is systemic therapy (i.e., chemotherapy and targeted therapy) with the most common chemotherapy used in the first-line setting being a combination of a platinum agent (e.g., cisplatin, oxaliplatin) and gemcitabine," he explained.
"The FOLFOX combination (5-fluorouracil and oxaliplatin) has shown modest activity in the second-line setting. Occasionally, there is a role for locoregional therapy to the liver, such as with radioembolization, or stereotactic body radiotherapy, but these decisions are made on an individual basis," Estfan observed. "Liver transplantation for certain patients with hilar cholangiocarcinoma is a viable option that may not be well-recognized.
"The main advances in cholangiocarcinoma management have been on the genomic and targeted therapy front," he noted. "Up to 30 percent of patients with cholangiocarcinoma have a potentially actionable mutation or genomic alteration, which can make them eligible for treatment with on- or off-label medications, or be candidates for clinical trials."
Two of the most prominent targetable mutations relevant to cholangiocarcinoma are fibroblast growth factor receptor 2 (FGFR2) and isocitrate dehydrogenase 1 (IDH1).
"Of those targeted therapies, both FGFR2 and IDH1 inhibitors have shown activity in the clinical setting," Estfan commented. "Pemigatinib, an FGFR2 inhibitor, was approved by the FDA for the treatment of advanced cholangiocarcinoma."
FGFR2 Inhibitor Pemigatinib
In April 2020, the FDA granted accelerated approval to the use of pemigatinib for adults with previously treated, unresectable locally advanced, or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement, as detected by an FDA-approved test. Their decision was largely based upon the results obtained in the FIGHT-202 (NCT02924376) clinical study (Lancet Oncol 2020;21(5):671-684).
In this Phase II, multicenter, open-label, single-arm trial, 107 patients were included who had unresectable, locally advanced, or metastatic cholangiocarcinoma who experienced disease progression on or after at least one prior therapy and had an FGFR2 gene fusion or rearrangement. During the study (January 2017 to March 2019), patients received 13.5 mg pemigatinib orally, once daily for 14 consecutive days, followed by 7 days off therapy for each 21-day treatment cycle.
The efficacy outcomes for this study were overall response rate (ORR) and duration of response (DOR), as determined by an independent review committee using RECIST 1.1 criteria. The ORR was 35.5 percent (95% CI: 27-45%) which included three complete responses and 35 partial responses. The median DOR was 9.1 months, and in 24 of the 38 responding patients (63%), responses lasted 6 months or more, while seven patients (18%) had responses of 12 months or longer.
The most frequently encountered adverse event (AEs), irrespective of cause and of any grade was hyperphosphatemia. A total of 64 percent of patients had grade 3 or worse AEs, of which the most common were hypophosphatemia, arthralgia, stomatitis, hyponatremia, abdominal pain, and fatigue. Serious AEs were noted in 45 percent of patients with the most frequent being abdominal pain, pyrexia, cholangitis, and pleural effusion. Fatalities occurred for 49 percent of the patients during the study; however, none of these were deemed to be treatment-related.
Regarding the FDA's action, it should be noted that the indication received accelerated approval based on the ORR and DOR efficacy outcomes. Continued approval for this indication may be contingent upon verification and description of clinical benefit in one or more subsequent confirmatory trials.
IDH1 Inhibitor Ivosidenib
Approximately 13 percent of patients with intrahepatic cholangiocarcinoma have disease characterized with mutations in IDH1. The central aim of the international Phase III ClarIDHy study (NCT02989857) was to assess the efficacy and safety of ivosidenib (also known as AG-120)-a small-molecule, orally bioavailable, targeted mutant IDH1 inhibitor-in patients with previously treated IDH1-mutated cholangiocarcinoma (Lancet Oncol 2020;21(6):796-807).
Patients were randomized in a 2:1 manner to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles. Crossover from placebo to ivosidenib was allowed for radiological progression per investigator assessment. The study's primary efficacy endpoint was progression-free survival (PFS) by independent central review.
Between February 2017 and January 2019, a total of 230 patients were assessed for eligibility, and as of the data cutoff date (January 31, 2019), 185 patients were randomized to ivosidenib (n=124) or placebo (n=61). The median follow-up for PFS was 6.9 months. Significant improvement for PFS was noted for ivosidenib compared with placebo (median: 2.7 months [95% CI: 1.6-4.2 months] vs. 1.4 months [1.4-1.6 months], respectively), affording a hazard ratio of 0.37 (95% CI: 0.25-0.54; one-sided p<0.0001).
In both treatment groups, the most common grade 3 or worse AE was ascites. Serious AEs were reported in 30 percent of patients receiving ivosidenib and 22 percent of patients receiving placebo; importantly, there were no treatment-related deaths. The results obtained in the study led the investigators to conclude that there was clinical benefit for targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma.
Treatment During COVID-19
When asked how COVID-19 had impacted his patients' treatment, Estfan replied, "We have seen some delays in patients getting diagnosed either due to delays in screening, fear of going to medical facilities and getting infected, or waiting on symptoms until it is too long.
"The COVID-19 pandemic has also affected the life of everybody, including patients. For some faced with terminal disease with little else to do outside of getting therapy, it further affects the mental health and the drive to be treated in certain situations. Patients who were admitted to the hospital at a certain time earlier in the year could not have visitors in person."
In discussing the safety measures for their patients, Estfan stated, "Our patients are careful overall and, while we know mortality tends to be higher in cancer patients with COVID-19, the rate of infections in cancer patients seemed to be less than the general population; many remain vigilant, adhering to established prevention guidelines."
"At Cleveland Clinic Cancer Center, we have remained open for cancer patients, including regular visits, consultations, and treatment," Estfan noted. "Discussing the measures taken at their practice, we have a robust task force that was formed immediately to ensure the safety of patients, providers, and continuity of care. We adapted to do more remote or virtual visits when needed. We had to innovate with treatment design and resource utilizations for a brief period, but thankfully I did not see any of my patients be denied what they needed in these testing times."
Richard Simoneaux is a contributing writer.