On May 14, 2020, experts in the management of patients with cholangiocarcinoma (CCA) convened for an accredited continuing education virtual symposium held during the Academy of Oncology Nurse & Patient Navigators (AONN+) 2020 Midyear Virtual Conference. Faculty included Richard Kim, MD, Senior Member and Section Chief, Gastrointestinal Medical Oncology, Moffitt Cancer Center, Tampa, FL, who provided an overview of CCA, current standards of care, and the use of FGFR and IDH1 inhibitors in the treatment of advanced CCA, and Lorraine Drapek, DNP, FNP-BC, AOCNP, Nurse Practitioner, Radiation Oncology/GI Services, Massachusetts General Hospital, Boston, who discussed the nurse’s role in preventing and managing adverse events associated with the use of newer targeted treatments. This article provides key highlights from this symposium.
Overview of CCA
CCA is a group of heterogeneous cancers that originate in the bile ducts that connect the liver and gallbladder to the small intestine.1 CCA is classified into 2 major types—intrahepatic and extrahepatic (including the perihilar and distal subtypes)—based on the location of the tumor relative to the liver. Approximately 10% of cases are intrahepatic, whereas the remaining cases are extrahepatic.1 CCA is relatively rare in the United States, with approximately 8000 new cases diagnosed each year.2
Risk Factors and Mortality
In Thailand and nearby regions, the most common predisposing cause of CCA is liver fluke infection, whereas in the Western world, it is primary sclerosing cholangitis.3,4 Other risk factors include gallstone disease, which causes infections in the bile ducts, as well as nonprimary sclerosing cholangitis cirrhosis, which is often associated with alcohol use, fatty liver disease, hepatitis B infection, or hepatitis C infection, and with an increased risk for CCA.5 Different environmental toxins or industrial toxins may also contribute to an individual’s risk for being diagnosed with CCA.6
CCA is among cancers with the worst survival. The overall 5-year survival rates for extrahepatic CCA and intrahepatic CCA are 10% and 9%, respectively.7
Clinical Presentation and Diagnosis
CCAs are typically asymptomatic during early stages. The most frequent symptom of perihilar CCA and distal CCA is jaundice caused by biliary tract obstruction. In intrahepatic CCA, jaundice is less frequent and mostly associated with advanced disease. Other symptoms of advanced disease include asthenia, abdominal pain, malaise, nausea, anorexia, and weight loss. Intrahepatic CCA is an incidental finding in approximately 20% to 25% of cases.8
Dr Kim noted that patients with CCA are usually not diagnosed at stage I. “Most patients are diagnosed with stage II, III, or IV disease,” he said. “Overall, the 5-year survival is very dismal.”
Imaging techniques, such as ultrasonography, contrast-enhanced ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI), play a key role in the management of CCA in terms of diagnosis, staging, follow-up, and assessment of treatment response.9 CT is considered the standard imaging method for the preoperative assessment of both intrahepatic CCA and perihilar CCA because it provides a comprehensive evaluation of the primary tumor, the relationship with adjacent structures, and potential thoracic and abdominal spread.9 MRI has similar accuracy to CT for diagnosis and staging, but it incorporates specific sequences such as diffusion-weighted imaging and the potential for performing magnetic resonance cholangiopancreatography, which are critical for the staging of perihilar CCA.10
There are several first-line treatment strategies for patients with CCA, including surgery and various chemotherapeutic regimens.11,12 Surgery, which is currently the only curative treatment for the disease, may involve the partial or entire removal of the bile duct and/or part of the liver, and should also include lymph node removal.13
Unfortunately, approximately 70% of patients with CCA are diagnosed at an advanced or metastatic stage, with only approximately one-third being eligible for surgical resection.11,14,15 For some patients with hilar CCA outside the liver that cannot be removed with surgery, a liver transplant may be a consideration.16 However, for most patients with unresectable CCA, the first-line treatment strategy is chemotherapy.
In the phase 3 ABC-02 clinical trial (N = 400), gemcitabine plus cisplatin was established as the standard first-line systemic therapy for advanced biliary cancers.17 This study enrolled patients with locally advanced or metastatic CCA, gallbladder cancer, or ampullary carcinoma and randomized them to either gemcitabine plus cisplatin or gemcitabine alone.
The primary end point was overall survival (OS), with key secondary end points including progression-free survival (PFS), tumor response, and safety. Early improvement in OS was observed and remained for up to 3 years of follow-up. The median OS was 11.7 months in the gemcitabine plus cisplatin group compared with 8.1 months in the gemcitabine-alone group.17
The single-arm, phase 2 GAP clinical trial (N = 60) evaluated the addition of nab-paclitaxel (Abraxane) to gemcitabine plus cisplatin in patients with advanced biliary tract cancers. The study population consisted predominantly of patients with intrahepatic CCA (63%) and metastatic CCA (78%), making it comparable to the ABC-02 study population. The median PFS and OS rates were 11.8 months and 19.2 months, respectively. The 12-month PFS rate was 45%.18
Grade ≥3 adverse events (AEs) occurred in 58% of patients, and 9 (16%) patients withdrew because of AEs. Neutropenia was the most common grade ≥3 AE, occurring in 19 (33%) patients overall. Although higher AE rates were observed in patients treated with the gemcitabine-cisplatin plus nab-paclitaxel regimen versus those treated with gemcitabine plus cisplatin, these were more common in the high-dose group.18
“One thing that is interesting in this trial is the fact that 20% of patients were converted from unresectable to resectable disease after getting full therapy, which is very encouraging,” Dr Kim said.
The randomized phase 3 S1815 clinical trial is also evaluating gemcitabine plus cisplatin with or without nab-paclitaxel in the first-line treatment of patients with advanced CCA or gallbladder cancer.19 Results from this trial are eagerly awaited and may have a major impact on the standard of care for CCA, adding a first-line option for patients who are able to tolerate a cytotoxic triplet regimen.
Relapse occurs in as many as two-thirds of patients with CCA following surgery,12 and there is currently no established standard of care after failure of first-line chemotherapy in patients with disease.20,21 Because most patients with CCA have disease progression, a number of retrospective analyses have been conducted to evaluate the efficacy of second-line treatments.20,22
The results of the randomized phase 3 ABC-06 study that enrolled 162 patients support the use of a FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin) regimen as a newer second-line standard of care in advanced biliary cancers.23 In this trial, patients with advanced biliary tract cancer who had disease progression on first-line gemcitabine plus cisplatin were randomized either to FOLFOX plus active symptom control (ASC) or ASC alone. The primary end point was OS. The difference in median OS between FOLFOX plus ASC and ASC alone (6.2 months vs 5.3 months, respectively) showed a modest, although statistically significant, improvement. The differences in OS rate at 6 months (50.6% vs 35.5%, respectively) and at 12 months (25.9% vs 11.4%, respectively) were clinically meaningful. A subgroup analysis showed consistent benefit across exploratory subgroups, with the greatest benefit reported in subgroups with poorer prognosis, including platinum-resistant patients, those with low albumin levels, and those with metastatic disease.
Novel Targeted Therapies
Multiple oncogenic molecular alterations, including FGFR and IDH mutations, have been identified in patients with CCA. Several of these mutations are being effectively targeted with novel treatments, paving the way for improved clinical outcomes, especially for patients with advanced or metastatic disease.
Dr Kim said that he is asking patients to get molecular profiling done as soon as they are diagnosed with metastatic CCA to look for actionable mutations. “Testing patients up front allows us to have a better plan for their treatment,” he said.
On April 17, 2020, the FDA granted accelerated approval to the selective FGFR inhibitor pemigatinib (Pemazyre) for adult patients with previously treated, unresectable locally advanced or metastatic CCA with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. This approval was based on results from the phase 2 FIGHT-202 trial of 107 patients with locally advanced unresectable or metastatic CCA associated with FGFR2 gene fusion or nonfusion rearrangement whose disease had progressed on or after ≥1 previous therapies.24
Patients in this trial received pemigatinib 13.5 mg orally once daily for 14 consecutive days, followed by 7 days off therapy. The overall response rate was 36%, including 3 complete responses. The median duration of response was 9.1 months, with responses lasting ≥6 months in 24 (63%) of the 38 responding patients and ≥12 months in 7 (18%) patients.
The most common AE observed with pemigatinib treatment was hyperphosphatemia. Other AEs included alopecia, dysgeusia, diarrhea, nausea, ocular effects, joint complaints, hypercalcemia, and skin and nail changes. Most AEs associated with pemigatinib are grade 1 or 2 in severity. If grade 3 or 4 AEs do occur, pemigatinib should be withheld until resolution of these toxicities.
On May 28, 2021, the FDA granted accelerated approval to infigratinib (Truseltiq) for the treatment of adult patients with previously treated, unresectable locally advanced or metastatic CCA with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. This approval was based on results of a single-arm, phase 2 trial of 108 patients with previously treated, advanced CCA, including 81% of patients with FGFR2 fusions.25
Patients in this trial received infigratinib 125 mg orally for 21 days of a 28-day cycle. Overall, 53.7% of the patients had received ≥2 previous lines of therapy; and all but 1 patient had stage IV disease. At a median follow-up of 11.3 months, the objective response rate was 23.1%, with 1 complete response and 24 partial responses reported. The median duration of response was 5.0 months (range, 0.9-19.1 months), and the median PFS was 7.3 months.
Patients who were less heavily pretreated achieved a better response, although there were still some responders among those who had received ≥2 previous lines of therapy. In a prespecified subgroup analysis of infigratinib in 50 patients who had received ≥1 line of previous therapy compared with 58 patients who had received ≥2 lines of previous therapy, the objective response rate was 34.0% and 13.8%, respectively.
The most common grade 3 or 4 AEs included stomatitis, hyponatremia, and hypophosphatemia.
Ivosidenib (Tibsovo) is a small-molecule inhibitor that is showing promise in the treatment of previously treated patients with IDH1-mutated CCA. In the global, randomized, double-blind, phase 3 ClarIDHy trial, 187 patients with CCA and IDH1 mutation were randomized to receive ivosidenib and 61 were randomized to receive placebo.26 Patients could cross over from the placebo arm to the ivosidenib arm at disease progression if they met eligibility criteria. In all, 70% of patients crossed over from placebo to ivosidenib. Nearly half (47%) of the patients in the study had received 2 previous lines of therapy. The median OS was 10.3 months with ivosidenib and 7.5 months with placebo. The adjusted median OS in the placebo arm was 5.1 months based on analysis using the rank-preserving structural failure time model (hazard ratio, 0.49; P <.0001).
All-grade treatment-emergent AEs in the ivosidenib arm included nausea, diarrhea, and fatigue. The rate of grade 3 or 4 AEs was 50% with ivosidenib and 37% with placebo. Only 7% of patients in the ivosidenib arm had AEs that led to treatment discontinuation.
Managing AEs Associated with Targeted Therapies
Dr Drapek discussed the management of AEs frequently seen with the use of FGFR and IDH1 inhibitors in recent clinical trials.
She stressed the fact that hyperphosphatemia is a common toxicity associated with the use of select FGFR inhibitors, noting that some patients who develop this AE require the use of sevelamer, a phosphate-binding medication. However, she said that there are other interventions that can be effective, such as putting patients on a low-phosphate diet.
“If you can give them a cookbook or recipes of low-phosphate meals, that would be helpful,” she noted.
Dr Drapek said that gastrointestinal toxicities are also common. Some patients may experience a lack of appetite, either related to nausea or changes in taste.
“They may not be able to tolerate certain foods due to treatment or advanced disease,” she said. “It is important that we keep these patients hydrated and ensure that they are getting enough protein.”
Diarrhea and constipation can usually be managed with appropriate medications or dietary changes.
“Magic mouthwashes” can be useful in cases of stomatitis. For dry mouth, artificial saliva or drugs that stimulate cholinergic agonists can be used. It is also recommended that patients use a lip balm for dry lips and lozenges for dry mouth.
Regarding ocular toxicities, Dr Drapek recommended that patients receive an ophthalmology evaluation at baseline and every 4 to 6 weeks after therapy, and then as needed. For dry eyes, artificial tears and warm eye masks can be helpful.
Patients should also be warned about skin and nail toxicities, which can sometimes be alarming, particularly if the nails detach from the nail bed. These toxicities can be treated with moisturizers prescribed by a dermatologist. In cases of infection, cephalexin or mupirocin ointment may be used. In patients with hand–foot syndrome, urea-containing creams are helpful. To prevent infection in patients with nail toxicities, daily soaking in vinegar is recommended. Topical antibacterials or topical steroids may be necessary in some cases.
Dr Drapek said that patients should be encouraged to engage in practices that can help them relax, such as aromatherapy, yoga, essential oils, journaling, or meditation. “These patients are going through so much. Self-care is very important,” she said.
- MedlinePlus. Cholangiocarcinoma. https://medlineplus.gov/genetics/condition/cholangiocarcinoma/. Updated June 1, 2020. Accessed June 16, 2021.
- Cancer.Net. Bile Duct Cancer (Cholangiocarcinoma): Statistics. www.cancer.net/cancer-types/bile-duct-cancer-cholangiocarcinoma/statistics. Updated January 2021. Accessed June 17, 2021.
- Prueksapanich P, Piyachaturawat P, Aumpansub P, et al. Liver fluke-associated biliary tract cancer. Gut Liver. 2018;12:236-245.
- Gatto M, Alvaro D. Cholangiocarcinoma: risk factors and clinical presentation. Eur Rev Med Pharmacol Sci. 2010;14:363-367.
- Bragazzi MC, Cardinale V, Carpino G, et al. Cholangiocarcinoma: epidemiology and risk factors. Transl Gastrointest Cancer. 2012;1:21-32.
- Mimaki S, Totsuka Y, Suzuki Y, et al. Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes. Carcinogenesis. 2016;37:817-826.
- American Cancer Society. Survival Rates for Bile Duct Cancer. www.cancer.org/cancer/bile-duct-cancer/detection-diagnosis-staging/survival-by-stage.html. Updated January 27, 2021. Accessed June 17, 2021.
- Alvaro D, Bragazzi MC, Benedetti A, et al. Cholangiocarcinoma in Italy: a national survey on clinical characteristics, diagnostic modalities and treatment. Results from the “Cholangiocarcinoma” committee of the Italian Association for the Study of Liver Disease. Dig Liver Dis. 2011;43:60-65.
- Joo I, Lee JM, Yoon JH. Imaging diagnosis of intrahepatic and perihilar cholangiocarcinoma: recent advances and challenges. Radiology. 2018; 288:7-13.
- Jhaveri KS, Hosseini-Nik H. MRI of cholangiocarcinoma. J Magn Reson Imaging. 2015;42:1165-1179.
- Rizvi S, Khan SA, Hallemeier CL, et al. Cholangiocarcinoma – evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15:95-111.
- Sardar M, Shroff RT. Biliary cancer: gateway to comprehensive molecular profiling. Clin Adv Hematol Oncol. 2021;19:27-34.
- Cancer.Net. Bile Duct Cancer (Cholangiocarcinoma): Types of Treatment. www.cancer.net/cancer-types/bile-duct-cancer-cholangiocarcinoma/types-treatment. Updated June 2020. Accessed June 17, 2021.
- Khan SA, Davidson BR, Goldin RD, et al; for the British Society of Gastroenterology. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut. 2012;61:1657-1669.
- Lamarca A, Barriuso J, McNamara MG, Valle JW. Biliary tract cancer: state of the art and potential role of DNA damage repair. Cancer Treat Rev. 2018;70:168-177.
- National Cancer Institute. Bile Duct Cancer (Cholangiocarcinoma) Treatment (PDQ)-Patient Version. www.cancer.gov/types/liver/patient/bile-duct-treatment-pdq. Updated October 1, 2020. Accessed June 17, 2021.
- Valle J, Wasan H, Palmer DH, et al; for the ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273-1281.
- Shroff RT, Javle MM, Xiao L, et al. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019;5:824-830.
- ClinicalTrials.gov. Gemcitabine hydrochloride and cisplatin with or without nab-paclitaxel in treating patients with newly diagnosed advanced biliary tract cancers. https://clinicaltrials.gov/ct2/show/NCT03768414. Accessed April 4, 2021.
- Lowery MA, Goff LW, Keenan BP, et al. Second-line chemotherapy in advanced biliary cancers: a retrospective, multicenter analysis of outcomes. Cancer. 2019;125:4426-4434.
- Ying J, Chen J. Combination versus mono-therapy as salvage treatment for advanced biliary tract cancer: a comprehensive meta-analysis of published data. Crit Rev Oncol Hematol. 2019;139:134-142.
- Lamarca A, Hubner RA, David Ryder W, Valle JW. Second-line chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol. 2014;25:2328-2338.
- Lamarca A, Palmer DH, Wasan HS, et al; for the Advanced Biliary Cancer Working Group. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22:690-701.
- Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020;21:671-684.
- Javle MM, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. J Clin Oncol. 2021;39(suppl). Abstract 265.
- Zhu AX, Macarulla T, Javle MM, et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. J Clin Oncol. 2021;39(suppl). Abstract 266.