The Lynx Group
Cholangiocarcinoma News

Managing Cholangiocarcinoma in the Setting of COVID-19: Unique Challenges and Opportunities

December 2020, Special Issue: Managing CCA in the Setting of COVID-19 — January 5, 2021
Ghassan K. Abou-Alfa, MD, MBA

Attending Physician
Memorial Sloan Kettering Cancer Center
New York, NY

Professor of Medicine
Weill Medical College at Cornell University
New York, NY

Bruce Lin, MD
Attending Physician
Section of Hematology/Oncology
Floyd & Delores Jones Cancer Institute
Virginia Mason Medical Center
Seattle, WA
Farshid Dayyani, MD, PhD
Professor of Clinical Medicine
Division of Hematology/Oncology
Department of Medicine, UC Irvine Health
Orange, CA
Richard Kim, MD
Senior Member and Section Chief, GI Medical Oncology
Department of Gastrointestinal Oncology, Moffitt Cancer Center
Tampa, FL
Rachna T. Shroff, MD, MS
Chief
Section of GI Medical Oncology, Director
UACC Clinical Trials Office, Director, Arizona Clinical Trials Network
Vice Chair for Clinical Research
Department of Medicine
Associate Professor of Medicine, Division of Hematology/Oncology
University of Arizona Cancer Center (UACC)
Tucson, AZ
Melinda Bachini
Director of Advocacy
Cholangiocarcinoma Foundation
Salt Lake City, UT
Milind M. Javle, MD
Professor
Department of Gastrointestinal Medical Oncology
Division of Cancer Medicine
The University of Texas
M.D. Anderson Cancer Center
Houston, TX
Chair
NCI Task Force: Hepatobiliary Cancers

Objectives

  • Ascertain the impact of coronavirus disease 2019 (COVID-19) on patient perceptions toward presenting symptoms of cholangiocarcinoma (CCA)
  • Discuss the impact of COVID-19 on clinical practice and clinical trial recruitment
  • Describe best practices for ensuring the safety of patients enrolled in clinical trials during the COVID-19 pandemic
  • Assess the impact of fibroblast growth factor receptor (FGFR) inhibitors on CCA treatment
  • Obtain perspectives on the use of molecular biomarker testing in patients with advanced, metastatic CCA, especially during the COVID-19 pandemic
  • Discuss supportive treatment of patients with CCA

The first confirmed case in the United States of the 2019 novel coronavirus (COVID-19) was reported on January 21, 2020, and as of November 27, 2020, there were >63 million confirmed cases and >1.5 million deaths globally (Figure 1).1-3 Despite the global impact, certain populations have been identified as having a higher risk of developing severe COVID-19 infection, including patients with cancer.4 Various studies have shown that patients with cancer experience particularly poor outcomes after COVID-19 infection.5-11 As a result of the pandemic, care delivery has been disrupted to some degree based on the need for prioritization and limitations on resources. Therefore, healthcare providers and patients have been continually reassessing the balance between the benefits and risks of anticancer interventions in the context of the added risk of COVID-19 infection.12

Figure 1

Challenges in the Medical Management of Patients with CCA

Many institutions have limited or postponed elective cancer procedures and have canceled outpatient clinics.13 Transportation disruptions and lockdowns have decreased access to diagnostic procedures (eg, biopsies), resulting in patients with cancer experiencing delays in diagnosis, staging, and therapy. This may contribute to increases in later-stage patients and those with metastatic disease seeking treatment and in the number of cancer-related deaths in the United States, including for gastrointestinal (GI) malignancies like gastric cancer and colorectal cancer (Figure 2),14 although similar data unique to CCA are not available. Additionally, the rate of depression has increased in patients with GI cancer because of quarantine and social distancing leading to more limited relationships with treating clinicians in combination with a lack of support from relatives.13

Figure 2

Psychosocial Impact

Because of the COVID-19 pandemic, many countries have implemented quarantine measures as the fundamental tool for disease control. As a result, there are both physical suffering and consequences on mental health and well-being at both the personal and population levels.15 The mass quarantine measures from nationwide lockdown programs may contribute to anxiety, distress, and mass hysteria because of a sense of being cornered and losing control. These feelings can be intensified if families are forced to separate as a result of uncertainty of disease progression, insufficient supply of basic essentials, financial loss, or increased perception of risk, which can be magnified by improper media communications and vague information in the early phase of a pandemic.16-18

Findings from previous outbreaks show that the psychological impact of quarantine can range from immediate effects, such as fear and frustration, to extreme consequences, including suicide.18-22 Postquarantine effects include socioeconomic distress and psychological symptoms as a result of financial loss.18 The psychosocial impact of COVID-19 varies among different strata of society (Figure 3).15

Figure 3

The Adoption and Use of Telehealth

To optimize patient and provider safety during the COVID-19 pandemic, telehealth has emerged as a “new normal” for patient engagement. The use of telehealth is a patient-centered approach that serves to protect patients, clinicians, and other medical staff.23,24 Telehealth is defined as the delivery of healthcare services by healthcare professionals, where distance is a critical factor, through the use of communication technologies for the exchange of valid information.25 After the evolution of portable electronics, most households have ≥1 appropriate devices, such as smartphones and webcams, that can be used to provide communication between the patient and provider.26,27 Telehealth use increased throughout March and April, reaching approximately 10% in September 2020 (Figure 4).28

Figure 4

There are several benefits to the use of telehealth technology, particularly in nonemergency or routine care cases where no direct patient–provider interaction is required.29 Care via telehealth decreases the use of resources, improves access to care, and decreases the risk of direct transmission of COVID-19 from person to person.30 Barriers to implementing telehealth include lack of or underreimbursement for telehealth visits by insurance, lack of patient access to an appropriate device, language barriers, and a technology literacy gap in which the patient may not be comfortable with telemedicine.31,32 Additionally, some clinicians may be concerned about clinical and technical quality, safety, privacy, and accountability.33,34 Changes in reimbursement have resulted in elimination of some telehealth barriers.35,36 Results from a single-institution experience with telehealth during the COVID-19 pandemic suggest that there are ways to overcome many of these barriers.32

Telehealth does not work for patients with CCA in all cases, including when imaging, procedures, and laboratory work are needed. In-person visits are required in these instances. However, clinicians may be able to reduce the need for face-to-face visits by changing dose intervals for infusion drugs, ordering less-frequent laboratory tests and imaging, or substituting oral medications where possible to reduce exposure for patients who require in-person visits.

By early April 2020, visits to ambulatory providers fell by approximately 60%, but have since returned to prepandemic levels (Figure 5).37 However, there are differences based on factors such as age, with younger-child visits remaining substantially below levels seen before the COVID-19 pandemic. Additionally, the percentage of all visits via telemedicine has been declining slowly since it peaked at approximately 14% in April 2020 but remains well above levels seen before the COVID-19 pandemic.

Figure 5

Molecular Biomarker Testing

Anatomic and molecular heterogeneity of CCA requires individual characterization of tumors at the molecular, genomic, and epigenetic levels to assess each person’s disease properly.38 Recommendations from the National Comprehensive Cancer Network (NCCN) include that all patients undergo microsatellite instability/mismatch repair testing and molecular testing as part of first-line management of metastatic CCA.39

Approximately 50% of patients with CCA carry a mutation that can be targeted using existing or emerging targeted therapies.40-42 The main targetable aberrations include isocitrate dehydrogenase (IDH) and FGFR among patients with intrahepatic CCA (iCCA), and HER2 among patients with extrahepatic CCA.43 Approximately 10% to 20% of iCCA patients harbor IDH1 mutations, and 10% to 20% of patients with iCCA have been reported to have FGFR2 fusions.41,42,44-46 FGFR2 alterations are more common than FGFR1 mutations, and rearrangements or fusions are more common than amplifications or mutations.43 Approximately 3.5% of patients with iCCA have NTRK fusions, and among patients with CCA, ≤8.7% harbor ROS1 fusions and 2.7% ALK fusions.43

Based on the difficult-to-biopsy nature of CCA, the access to tumor tissue can provide a barrier to biomarker testing. During the COVID-19 pandemic, access to tumor tissue may prove even more difficult, leading to decreased diagnoses and decreased molecular biomarker testing.28 Therefore, cell-free DNA (cfDNA) detection in plasma samples has been evaluated for guiding therapeutic interventions, although this method currently remains investigational.38 In an analysis of patients with biliary tract cancer, circulating tumor (ct)DNA from blood exhibited 74% concordance with tissue DNA, and the concordance was 92% among patients with iCCA.47 One of the main disadvantages to the use of liquid biopsy is the varying levels of cfDNA among patients, which may compromise the reliability and accuracy of the tests. Furthermore, typical genomic DNA can be found in cfDNA, requiring highly sensitive detection and identification of mutations with the need for validation to determine that the results are clinically actionable.48,49 Currently, liquid biopsy is rarely considered an option for use in clinical trials.43

For patients with cancer in the community,50 various barriers to biomarker testing have been identified, including the following:

  • High cost of testing
  • Prolonged turnaround time for results (≥3-4 weeks)
  • Limited accessibility to tissue
    • Preanalytic issues with tissue may also be a barrier because of variations in procurement, fixation, processing, and the storage of specimens.51
  • Lack of standardization in biomarker testing
  • Siloed disciplines resulting in low rates of biomarker testing
    • To improve biomarker testing rates and increase standardization, communication across silos or disciplines is needed to ensure alignment on how to determine each patient’s biomarker status.50
  • Lengthy complex reports that are difficult to interpret
    • One of the primary complaints related to next-generation sequencing (NGS) reports is that they are too long, and half of the information is not valuable to the clinician.50
  • Lack of education for providers on guidelines

Newly released guidelines on NGS testing by the European Society for Medical Oncology Precision Medicine Working Group in CCA recommend multigene tumor NGS, with a shift to RNA-based testing, to drive treatment decisions in daily practice.52

A Patient Advocate Perspective on Biomarker Testing

Biomarker testing in CCA has provided patients more options for treatment. Approximately 50% of patients with CCA have a targetable mutation that could be treated in a clinical trial, with off-label treatments, through expanded access, or with approved therapies.40 Biomarker testing should become the standard practice for all patients on diagnosis. This testing provides opportunities for patients to enroll in first-line clinical trials if available, and it also provides a road map for treatment plans.

Therapeutic Challenges During COVID-19

Patients with CCA are often diagnosed at later stages of disease because those with early disease are either asymptomatic or present with nonspecific symptoms that cannot be immediately attributed to biliary tract cancers.53,54 As a result, CCA is difficult to diagnose and treat, contributing to a poor prognosis, with indirect effects of local tumor progression, bile duct obstruction, liver failure, or sepsis from cholangitis and abscess. The 5-year relative survival rate for patients with all stages of CCA is between 8% (intrahepatic) and 10% (extrahepatic), requiring prompt and aggressive treatment to improve patient outcomes.55

Patients with CCA require various procedures related to diagnosis and treatment of CCA and associated issues. Histopathologic or cytologic analysis is required for confirming the diagnosis.54,56 Endoscopic techniques are used for the diagnosis of CCA to provide symptomatic relief, identify tumor characteristics, and assess the potential for nonsurgical interventions. Special considerations or precautions are necessary for these procedures during the COVID-19 era. Biliary stenting for acute cholangitis in patients with CCA should be individualized based on patient and tumor factors.57 Among patients who require stenting and test positive for COVID-19, a percutaneous transhepatic drain can be placed during conscious sedation if appropriate personal protective equipment (PPE) is not available.57 The timing of biliary stent replacement depends on each institution’s guidelines. Endoscopically assisted procedures and percutaneous biliary drainage are potential options during the COVID-19 pandemic with appropriate COVID-19 screening and protection using PPE, considering the aerosol-generating potential.

Individual centers have reported delaying nonurgent or elective surgeries during periods with peak COVID-19 cases.58,59 From March to July 2020, US hospitals reported an average 35% decrease in operating room volumes, and are expected to remain below 2019 levels for the remainder of the year (Figure 6).60 It is not clear how these delays may impact cancer progression and patient outcomes; however, results from a modeling study of 94,912 patients undergoing resections for major cancers annually suggest that a 3-month delay of surgery across cancers of stages I to III would contribute to 4755 deaths attributable to the delay, and a 6-month delay would contribute to 10,760 deaths attributable to the delay.61 The current focus of surgical oncologists and multidisciplinary teams is to prioritize surgeries using clinical rationale and potential strategies for nonsurgical management, with the decisions based on available resources.62

Figure 6

As a result of the pandemic, the medical community has been forced to prioritize and explore alternative, noninvasive treatment approaches for patients with GI cancer.13 In patients with advanced cancer, chemotherapy is initiated or continued despite the associated immunosuppression that heightens the risk of increased morbidity and death due to COVID-19 infection.13 Results from an analysis of 423 patients with cancer who were diagnosed with COVID-19 showed that non-white race, hematologic malignancy, a composite measure of chronic lymphopenia and/or corticosteroid use, and treatment with immune checkpoint inhibitor therapy were independently associated with hospitalization related to COVID-19.63 Furthermore, treatment with immune checkpoint inhibitor therapy was an independent predictor of severe respiratory illness. Of note, there was no significant association of either major surgery or recent chemotherapy (within 30 days), or metastatic disease with either hospitalization or severe respiratory illness because of COVID-19. Until additional studies have been completed, it would be unwise to alter treatment decisions; instead, most providers consider increased vigilance with testing for COVID-19 in patients who start or continue immune checkpoint inhibitor therapy regardless of symptoms.63

Based on the decreased access to operating facilities during the COVID-19 pandemic, alternative strategies may be required for patients on an individualized basis after multidisciplinary discussion.57 Neoadjuvant systemic therapy can be considered for an extended time until resources are available for patients who require downstaging for resectability of their tumor despite the lack or limited evidence of improved outcome with such an approach. Alternative therapies for small, unresectable iCCA include radiofrequency or microwave ablation, which have been shown to provide good local tumor control in patients with lesions that are ≤5 cm in diameter.57 For peripheral lesions, stereotactic body radiotherapy and proton beam therapy may be considered, with the option for hypofractionated radiotherapy for more centrally located disease. When surgery is not an option, neoadjuvant chemotherapy, radiotherapy, or transarterial radioembolization may be considered for larger, localized iCCA.

Standard-of-care locoregional therapies include local ablation or radiotherapy in selected patients and transarterial chemoembolization, embolization, and radioembolization.57 Interventional radiology interventions may be decreased during COVID-19, but they are highly effective for control of local tumors and require single-day procedures. In areas with reduced or unavailable interventional resources, radiotherapy may be considered for tumors of ≤10 cm in diameter, ensuring that liver dose-volume constraints are met.57

Bridging therapy with intravenous gemcitabine-based chemotherapy was thought not to be ideal to administer during the COVID-19 pandemic based on increased immunosuppressive risk and the requirement for additional visits to infusion centers, clinics, or hospitals for managing side effects.57 It may be reasonable to postpone adjuvant chemotherapy for ≤16 weeks after surgery to minimize patients’ exposure to healthcare settings. However, it has been shown that there is no association between recent chemotherapy delivery and hospitalization among patients with cancer diagnosed with COVID-19.63

Among patients with incurable iCCA, the standard-of-care regimen is a combination of cisplatin and gemcitabine. During the COVID-19 pandemic, some experts have suggested the modification of the dosing regimen to days 1 and 14 of a 28-day cycle to reduce the number of visits to infusion centers and the immunosuppressive effects of the treatment, even though this modification remains unsubstantiated.57,64 It has been suggested that surveillance and best supportive care or single-fraction radiotherapy may be considered for symptomatic disease.57

The use of systemic therapy during the COVID-19 pandemic should be determined based on decisions considering routine oncology care and treatment effects on the immune system.62 Shared decision-making discussions with patients should include evidence-based benefits of treatment and the risk of COVID-19 infection after clinic attendance for cancer-directed therapy.65 Therapies with curative potential or substantial improvements in outcomes should not be delayed; this would include many therapies for patients with CCA. Therapies with incremental benefits require discussion of the associated risks and benefits and consideration of the prevalence of COVID-19 in the local setting.62

For patients with a targetable mutation (eg, IDH1-mutated or FGFR2 translocated iCCA), access to orally administered selective inhibitors has been recommended whenever feasible.42,66-68

Results from an open-label, phase 2 study of 146 patients with previously treated, locally advanced, or metastatic CCA with FGFR2 fusions or rearrangements treated with pemigatinib showed an overall response rate (ORR) of 35.5%, a disease control rate (DCR) of 82%, and median progression-free survival (PFS) of 6.9 months.42 In April 2020, the US Food and Drug Administration (FDA) granted accelerated approval to pemigatinib as second-line treatment in adults with previously treated, unresectable, locally advanced, or metastatic CCA with an FGFR2 fusion or other rearrangement, as detected by an FDA-approved test.69

Other FGFR inhibitors are in late-stage clinical development. For example, in an open-label, phase 2 study, treatment with infigratinib, a selective inhibitor of FGFR, led to an ORR of 31%, DCR of 83.6%, and median PFS of 6.8 months in patients with advanced or metastatic CCA with FGFR2 fusions or other alterations after progression on prior therapy.41,70 Moreover, results from a multicenter, phase 2 study of 67 patients treated with futibatinib showed an ORR of 37.3%, a DCR of 82.1%, and a median PFS of 7.2 months.71,72 In addition, data from a clinical study with derazantinib, an orally bioavailable, multikinase inhibitor with pan-FGFR activity, showed an ORR of 20.7%, DCR of 82.8%, and median PFS of 5.7 months in patients with advanced, unresectable iCCA with FGFR2 fusions who progressed after chemotherapy.67

In CCA, data on immunotherapy are currently limited. In certain patients, immune checkpoint blockade has resulted in durable response rates; 40% of patients with mismatch repair-deficient tumors achieved objective responses, including some patients with CCA.73 Ongoing and planned clinical trials have been designed to investigate combination immunotherapeutic approaches that target the innate and adaptive immune systems and/or combination strategies that involve radiation or chemotherapy. Immunotherapy, when administered for pulmonary metastases, may increase COVID-19 complications.63

A Patient Advocate Perspective on Treatment for CCA During the COVID-19 Pandemic

A diagnosis of CCA is scary enough, let alone during a pandemic! And depending on where a patient is diagnosed, COVID-19 means that he or she will have additional decisions to make. For example, if the newly diagnosed individual happens to be fortunate enough to be a surgical candidate, will he or she have to travel for surgery? Is the center or institution to which the patient must travel even performing surgeries? Some hospitals have implemented restrictions, and often it was difficult to obtain information regarding what hospital services were open and which patients were still being seen. In virus hot spots, staff were pulled from their specialties and deployed to help manage an expected influx of patients. As hospitals tightened the scope of their services, they inevitably tightened regulations on access. This led to new concerns and questions for patients. Suddenly, the possibility of patients’ ability to bring a caregiver with them to appointments was in doubt. Will patients be able to have a family member or friend with them before surgery? During recovery? As patients, it is vital to have caregivers and advocates at their side to remember important information that is shared by your medical providers. Unfortunately, COVID-19 has placed limitations on this necessity. The Director of Advocacy for the Cholangiocarcinoma Foundation has heard from patients who have had to recover from infections, complications, and surgeries alone in the hospital because of COVID-19 restrictions.

The imposed adopted telehealth venue helped patients to access second opinions from experts via telehealth. For the first time, patients are able to receive second opinions in the comfort of their own homes without incurring time away, travel costs, or additional stress. Thus, because consultations are now being offered by remote, online visits, it is anticipated that more patients with CCA may be getting second opinions from experts in this field. Where it used to be a financial burden to travel to another area for a second opinion, patients can now send their records for review and meet via accessible telehealth visits. This provides patients with greater access to specialists, offers expert opinions on treatment plans, and allows for collaborations between experts in the field and community oncologists.

The Impact of COVID-19 on Recruitment and Conduct of Clinical Trials

Results from a survey of 32 investigators conducted by the American Society of Clinical Oncology (ASCO) provided information regarding what investigators were observing and feeling early in the pandemic (late March 2020), and may serve as motivation for facilitating changes to improve the clinical research system.74 One of the most widely adopted solutions to seeing patients and ensuring the safety of their care was telemedicine. Most investigators who responded noted that their institutions developed policies related to the COVID-19 pandemic, with 75% of programs mandating research staff to work remotely. Delays in clinical research activities were also common, with many programs stopping cancer screening and/or enrollment for clinical trials. More than 54% of respondents reported a decreased patient ability or willingness to visit their site, with additional challenges due to staff time needed to organize, implement, and conduct telehealth visits.74

Results from another survey-based study of 36 investigators conducted between March 23 and April 3 were consistent with these findings, with decreased enrollment of patients in active clinical trials during the study period.75 Only 20% and 14% of institutions in the United States and Europe, respectively, continued to enroll patients at the usual rate. These results also supported the adoption of technology-based interventions, including telemedicine, remote access to the electronic medical records, and virtual monitoring of data and study documentation. In an additional analysis of >200 oncology clinical trials, milestone delays were the most commonly reported risk due to the pandemic, likely caused by delays to site activation, enrollment, patient visits, and/or data collection and cleaning. Furthermore, >200 interventional oncology studies were suspended because of COVID-19 in March and April 2020.75

The COVID-19 pandemic has created many challenges related to planning and conducting clinical trials. As of March 26, 2020, ≥18 biotechnology and pharmaceutical companies reported a disruption to a clinical trial because of the COVID-19 pandemic.76 For ongoing trials, the main concern surrounds patient safety. Many patients enrolled in clinical trials may be vulnerable to infection and traveling to clinical trial sites may be detrimental if the patient is exposed to COVID-19. Additionally, some patients require intensive assessments that are difficult to complete during the pandemic without in-person visits, including undergoing imaging and obtaining samples for laboratory analysis. Additional risks include patient unwillingness to enroll in new trials, dropout, and noncompliance as a result of travel restrictions and quarantined areas. Results from a recent survey-based study showed that 39% of US sites believe that patients will be much less or somewhat less likely to enroll in new clinical trials. Patients may also be anxious and hesitant to visit healthcare facilities, with additional considerations of the contamination risk among patients, sites, and the community.76

There are both immediate and delayed consequences of the COVID-19 pandemic on the conduct of clinical trials, including reduced recruitment, delayed assessment of end points because of missed visits, and increased protocol deviations that may affect patient safety because of missing or late reporting of adverse events.77 Investigators and sponsors should consider withdrawal of optional procedures and facilitate assessments to be completed at an accredited facility near the patient. Alternative safe delivery methods should be implemented for oral medications or other medications distributed for self-administration to avoid the need for patients to visit hospitals.

One solution to the challenges related to clinical trials during the COVID-19 pandemic is to bring the trial to the patient by deploying in-home clinical services to ensure patient and staff safety.76 In September 2020, the FDA published an updated guidance advising sponsors to investigate alternative methods of safety assessments for patients that can be deployed during times when travel to clinical trial sites is restricted.78 Having healthcare providers visit the patient at home may reduce anxiety while increasing comfort and convenience. Furthermore, in-home services contribute to reduced travel burden and risk of patient dropout and enhanced compliance, data collection, and retention.

ASCO released a position statement on home infusion of anticancer therapy on June 23, 2020. According to ASCO, the decision to administer anticancer therapy in a home setting should be the result of shared decision-making between the treating physician and the patient after consideration of the precautions needed to protect medical staff, patients, and caregivers from adverse events related to drug infusion and disposal. In general, ASCO does not recommend home infusion of anticancer therapy.79

The FDA provided guidance for active clinical trials, noting that sponsors and clinical investigators should engage with institutional review boards/independent ethics committees as soon as possible when urgent or emergent changes to the protocol or informed consent are anticipated because of COVID-19.78 However, these changes may be implemented without institutional review board approval, but are required to be reported afterward. Furthermore, because changes in study visit schedules or patient discontinuations may lead to missing information, it is important to capture specific information explaining the basis of the missing data (eg, from missed study visits or study discontinuations because of COVID-19).

A Patient Advocate Perspective on Recruiting and Conducting Clinical Trials in CCA During the COVID-19 Pandemic

The Director of Advocacy for the Cholangiocarcinoma Foundation reflects on her long survivorship with stage IV CCA and celebrates the multiple opportunities to speak to and interact with patients and caregivers daily worldwide. Her perspective on recruiting and conducting clinical trials in CCA during the COVID-19 pandemic is varied. The only constant amid COVID-19 is that patients have been greatly affected. In the beginning of the pandemic, several hurdles were observed that patients faced in gaining access to clinical trials. Specifically, many patients were fearful of travel. Under normal circumstances, patients with cancer who are immune compromised are very cautious travelers. This was exasperated by the pandemic. The situation was made further difficult by the fact that most institutions were not accepting new patients. Because travel was very much an issue for patients to get to a site conducting a clinical trial, patients felt their opportunities for finding treatment were extremely limited. Moreover, many patients reached a point in their treatment(s) in which chemotherapy was no longer working and they were ready to enroll in a trial but had to postpone enrollment because of difficult access in a participating site. Although this may not have been the case with all hospitals associated with cancer centers, the barriers posed by travel—especially safe travel—meant that patients’ ability to access services was limited. Although many of the worst-case scenarios did not materialize, these scenarios did, at a minimum, mentally and emotionally affect patients who had to travel for trials. Currently, it appears that patients are more willing to travel and enroll in trials.

Conclusions

The COVID-19 pandemic has presented multiple challenges related to the treatment of patients with CCA. With decreased office visits and diagnostic procedures, it is likely that fewer patients are receiving timely diagnoses and subsequent treatment, which may contribute to poorer outcomes. Telehealth has emerged as an option for physicians to maintain contact with patients while ensuring their safety and the safety of medical staff.

Systemic chemotherapy may not be perceived as safe for patients during the COVID-19 pandemic because of risks of potential COVID-19 exposures while traveling or in a clinic or hospital setting to receive infusions and the possible need for additional medical support. However, these treatments are needed to control disease and help to improve patient outcomes. If applicable, oral therapies may be mailed to provide an alternative for certain patients.

Many clinicians express their preparedness for another wave of COVID-19 infection based on the fact that protocols for patient testing and treatment have been put in place with the requirements for appropriate PPE. Overall, for patients with CCA, clinician preparedness for ensuring safety throughout the management continuum is increased after the first wave of COVID-19.

Summary

  • During the COVID-19 pandemic, there has been a decrease in US cancer diagnoses because of multiple factors, including a reluctance of patients to travel to a cancer center and a decrease in the performance of procedures required to confirm a cancer diagnosis
  • The rate of depression has increased in patients with GI cancer because of quarantine and social distancing, leading to more limited relationships with treating clinicians
  • Care via telehealth decreases the use of resources, improves access to care, and decreases the risk of community transmission of COVID-19
  • Based on the difficult-to-biopsy nature of CCA, access to tumor tissue can provide a barrier to biomarker testing. During the COVID-19 pandemic, access to tumor tissue may prove even more difficult, leading to both decreased diagnoses and molecular biomarker testing
  • Therapies with curative potential or substantial improvements in outcomes should not be delayed, including those for patients with CCA. Therapies with incremental benefits require discussion of the associated risks and benefits and consideration of the prevalence of COVID-19 in the local setting
  • There are both immediate and delayed consequences of the COVID-19 pandemic on the conduct of clinical trials, including reduced recruitment, delayed assessment of end points because of missed visits, and increased protocol deviations that may affect patient safety because of missing or late reporting of adverse events

Don’t miss out. Stay up to date with the latest news on cholangiocarcinoma, biliary tract cancer, and gallbladder cancer with a subscription to CCA News.

References

  1. The American Journal of Managed Care. A Timeline of COVID-19 Developments in 2020. July 3, 2020. www.ajmc.com/view/a-timeline-of-covid19-elopments-in-2020. Accessed September 11, 2020.
  2. Johns Hopkins University & Medicine. Coronavirus resource center. coronavirus.jhu.edu/map.html. Last updated November 19, 2020. Accessed November 19, 2020.
  3. World Health Organization (WHO). WHO Coronavirus Disease (COVID-19) Dashboard. Website. https://covid19.who.int. Last updated November 19, 2020. Accessed November 19, 2020.
  4. Centers for Disease Control and Prevention. People with Certain Medical Conditions. www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/ple-with-medical-conditions.html. Updated November 2, 2020. Accessed November 19, 2020.
  5. Garassino MC, Whisenant JG, Huang LC, et al; TERAVOLT investigators. COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study. Lancet Oncol. 2020;914-922.
  6. Giannakoulis VG, Papoutsi E, Siempos II. Effect of cancer on clinical outcomes of patients with COVID-19: a meta-analysis of patient data. JCO Glob Oncol. 2020;6:799-808.
  7. Kuderer NM, Choueiri TK, Shah DP, et al; COVID-19 and Cancer Consortium. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet. 2020;395:1907-1918.
  8. Pinato DJ, Zambelli A, Aguilar-Company J, et al. Clinical portrait of the SARS-CoV-2 epidemic in European cancer patients. Cancer Discov. 2020:CD-20-0773.
  9. Rivera DR, Peters S, Panagiotou OA, et al; COVID-19 and Cancer Consortium. Utilization of COVID-19 treatments and clinical outcomes among patients with cancer: a COVID-19 and Cancer Consortium (CCC19) cohort study. Cancer Discov. 2020;10:1514-1527.
  10. Saini KS, Tagliamento M, Lambertini M, et al. Mortality in patients with cancer and coronavirus disease 2019: a systematic review and pooled analysis of 52 studies. Eur J Cancer. 2020;139:43-50.
  11. Westblade LF, Brar G, Pinheiro LC, et al. SARS-CoV-2 viral load predicts mortality in patients with and without cancer who are hospitalized with COVID-19. Cancer Cell. 2020;38:661-671.
  12. Schrag D, Hershman DL, Basch E. Oncology practice during the COVID-19 pandemic. JAMA. 2020;323:2005-2006. 
  13. Tsamakis K, Gavriatopoulou M, Schizas D, et al. Oncology during the COVID-19 pandemic: challenges, dilemmas and the psychosocial impact on cancer patients. Oncol Lett. 2020;20:441-447.
  14. Kaufman HW, Chen Z, Niles J, Fesko Y. Changes in the number of US patients with newly identified cancer before and during the Coronavirus Disease 2019 (COVID-19) pandemic. JAMA Netw Open. 2020;3:e2017267.
  15. Dubey S, Biswas P, Ghosh R, et al. Psychosocial impact of COVID-19. Diabetes Metab Syndr. 2020;14:779-788.
  16. Maunder R, Hunter J, Vincent L, Bennett J, Peladeau N, Leszcz M. The immediate psychological and occupational impact of the 2003 SARS outbreak in a teaching hospital. CMAJ. 2003;168:1245-1251.
  17. Hawryluck L, Gold WL, Robinson S, Pogorski S, Galea S, Styra R. SARS control and psychological effects of quarantine, Toronto, Canada. Emerg Infect Dis. 2004;10:1206-1212. 
  18. Brooks SK, Webster RK, Smith LE, Woodland L, Wessely S, Greenberg N. The psychological impact of quarantine and how to reduce it: rapid review of the evidence. Lancet. 2020;395:912-920. 
  19. Robertson E, Hershenfield K, Grace SL, Stewart DE. The psychosocial effects of being quarantined following exposure to SARS: a qualitative study of Toronto health care workers. Can J Psychiatr. 2004;49:403-407.
  20. Barbisch D, Koenig KL, Shih FY. Is there a case for quarantine? Perspectives from SARS to Ebola. Disaster Med Public Health Prep. 2015;9:547-553.
  21. Jeong H, Yim HW, Song YJ, et al. Mental health status of people isolated due to Middle East respiratory syndrome. Epidemiol Health. 2016;38:e2016048.
  22. Liu X, Kakade M, Fuller CJ, Fan B, Fang Y, Kong J. Depression after exposure to stressful events: lessons learned from the severe acute respiratory syndrome epidemic. Compr Psychiatr. 2012;53:15-23.
  23. Kruse CS, Krowski N, Rodriguez B, Tran L, Vela J, Brooks M. Telehealth and patient satisfaction: a systematic review and narrative analysis. BMJ Open. 2017;7:e016242. 
  24. Dorsey E, Topol E. State of telehealth. N Engl J Med. 2016;375:154-161.
  25. World Health Organization (WHO). Telemedicine: opportunities and developments in member states. Report on the second global survey on eHealth. 2010. www.who.int/goe/publications/goe_telemedicine_2010.pdf. Accessed November 19, 2020.
  26. Valle J, Godby T, Paul III DP, Smith H, Coustasse A. Use of smartphones for clinical and medical education. Health Care Manag. 2017;36:293-300. 
  27. Jahanshir A, Karimialavijeh E, Sheikh H, Vahedi M, Momeni M. Smartphones and medical applications in the emergency department daily practice. Emergency. 2017;5:e14.
  28. IQVIA. Medical claims data analysis. Monitoring the impact of COVID-19 on the pharmaceutical market. November 6, 2020.
  29. Fortney JC, Pyne JM, Edlund MJ, et al. A randomized trial of telemedicine-based collaborative care for depression. J Gen Intern Med. 2007;22:1086-1093.
  30. Charles BL. Telemedicine can lower costs and improve access. Healthc Financ Manage. 2000;54:66.
  31. Hollander JE, Carr BG. Virtually perfect? Telemedicine for Covid-19. N Engl J Med. 2020;382:1679-1681.
  32. Barney A, Buckelew S, Mesheriakova V, Raymond-Flesch M. The COVID-19 pandemic and rapid implementation of adolescent and young adult telemedicine: challenges and opportunities for innovation. J Adolesc Health. 2020;67:164-171.
  33. Greenhalgh T, Koh GCH, Car J. Covid-19: a remote assessment in primary care. BMJ. 2020;368:m1182.
  34. Greenhalgh T, Wherton J, Shaw S, Morrison C. Video consultations for Covid-19. BMJ. 2020;368:m998. 
  35. Centers for Medicare and Medicaid Services (CMS). Medicare telemedicine health care provider fact sheet. May 17, 2020. www.cms.gov/newsroom/fact-sheets/medicare-telemedicine-health-care-provider-fact-sheet. Accessed November 18, 2020.
  36. America’s Health Insurance Plans (AHIP). Health Insurance Providers Respond to Coronavirus (COVID-19). AHIP website. www.ahip.org/health-urance-providers-respond-to-coronavirus-covid-19. Accessed November 18, 2020.
  37. Mehrotra A, Chernew M, Linetsky D, et al. The impact of the COVID-19 pandemic on outpatient care: visits return to prepandemic levels, but not for all providers and patients. October 15, 2020. www.commonwealthfund.org/lications/2020/oct/impact-covid-19-pandemic-outpatient-care-visits-urn-prepandemic-levels. Accessed November 18, 2020.
  38. Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17:557-588.
  39. NCCN. Clinical Practice Guidelines in Oncology. Hepatobiliary cancers, version 4.2020. www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed September 9, 2020.
  40. Avogadri F, Wei G, Dambkowski C, et al. Molecular tumor profiling identifies actionable targets in patients with cholangiocarcinoma. Presented at the AACR Virtual Annual Meeting, June 22-24, 2020. Abstract 2940.
  41. Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36:276-282.
  42. 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.
  43. Lamarca A, Barriuso J, McNamara MG, Valle JW. Molecular targeted therapies: ready for “prime time” in biliary tract cancer. J Hepatol. 2020;73:170-185.
  44. Ross JS, Wang K, Gay L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist. 2014;19:235-242.
  45. Farshidfar F, Zheng S, Gingras MC, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 2017;8:2780-2794.
  46. Graham RP, Barr Fritcher EG, Pestova E, et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol. 2014;45:1630-1638.
  47. Ettrich TJ, Schwerdel D, Dolnik A, et al. Genotyping of circulating tumor DNA in cholangiocarcinoma reveals diagnostic and prognostic information. Sci Rep. 2019;9:13261.
  48. Arneth B. Update on the types and usage of liquid biopsies in the clinical setting: a systematic review. BMC Cancer. 2018;18:527. 
  49. Molina-Vila MA, Mayo-de-Las-Casas C, Giménez-Capitán A, et al. Liquid biopsy in non-small cell lung cancer. Front Med (Lausanne). 2016;3:69.
  50. Sundin T. Biomarker testing for cancer patients: barriers and solutions. June 15, 2020. labmedicineblog.com/2020/06/15/biomarker-testing-for-cancer-ients-barriers-and-solutions-part-6. Accessed September 22, 2020.
  51. Bass BP, Engel KB, Greytak SR, Moore HM. A review of preanalytical factors affecting molecular, protein, and morphological analysis of formalin-fixed, paraffin-embedded (FFPE) tissue: how well do you know your FFPE specimen? Arch Pathol Lab Med. 2014;138:1520-1530.
  52. Mosele F, Remon J, Mateo J, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol. Published online August 24, 2020. doi:10.1016/j.annonc.2020.07.014.
  53. Patel T. Cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol. 2006;3:33-42.
  54. Bridgewater J, Galle PR, Khan SA, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014;60:1268-1289.
  55. American Cancer Society. Survival Rates for Bile Duct Cancer. www.cer.org/cancer/bile-duct-cancer/detection-diagnosis-staging/survival-by-ge.html. Updated January 8, 2020. Accessed October 25, 2020.
  56. Banales JM, Marin JJG, Lamarca A, et al. Expert consensus document. Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016;13:261-280.
  57. Barry A, Apisarnthanarax S, O’Kane GM, et al. Management of primary hepatic malignancies during the COVID-19 pandemic: recommendations for risk mitigation from a multidisciplinary perspective. Lancet Gastroenterol Hepatol. 2020;5:765-775.
  58. Chang EI, Liu JJ. Flattening the curve in oncologic surgery: impact of Covid-19 on surgery at tertiary care cancer center. J Surg Oncol. 2020 Jun 2:10.1002/jso.26056. doi:10.1002/jso.26056.
  59. Morrison DR, Gentile C, McCammon S, Buczek E. Head and neck oncologic surgery in the COVID-19 pandemic: our experience in a deep south tertiary care center. Head Neck. 2020;42:1471-1476.
  60. McKinsey & Company. Healthcare Systems and Services Practice. Cutting through the COVID-19 surgical backlog. October 2020:1-8. www.mckinsey.com/~/media/McKinsey/Industries/Healthcare%20Systems%20and%20vices/Our%20Insights/Cutting%20through%20the%20COVID%2019%20surgical%20backlog/Cutting-through-the-COVID-19-surgical-backlog.?shouldIndex=false. Accessed November 11, 2020.
  61. Sud A, Jones ME, Broggio J, et al. Collateral damage: the impact on outcomes from cancer surgery of the COVID-19 pandemic. Ann Oncol. 2020;31:5-1074.
  62. Bakouny Z, Hawley JE, Choueiri TK, et al. COVID-19 and cancer: current challenges and perspectives. Cancer Cell. 2020 Oct 1:S1535-6108(20)30492-X. doi:10.1016/j.ccell.2020.09.018.
  63. Robilotti EV, Babady NE, Mead PA, et al. Determinants of COVID-19 disease severity in patients with cancer. Nat Med. 2020;26:1218-1223.
  64. Ahn DH, Reardon J, Ahn CW, et al. Biweekly cisplatin and gemcitabine in patients with advanced biliary tract cancer. Int J Cancer. 2018;142:1671-1675.
  65. Gharzai LA, Resnicow K, An LC, Jagsi R. Perspectives on oncology-specific language during the Coronavirus Disease 2019 pandemic: a qualitative study. JAMA Oncol. 2020;6:1424-1428.
  66. Lowery MA, Burris HA 3rd, Janku F. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol. 2019;4:711-720.
  67. 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.
  68. Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;796-807.
  69. US Food and Drug Administration (FDA). FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. News release. April 17, 2020. www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion. Accessed September 22, 2020.
  70. 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. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA28.
  71. Goyal L, Meric-Bernstam F, Hollebecque A, et al. FOENIX-CCA2: a phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements. J Clin Oncol. 2020;35(suppl 15):108.
  72. Bridgewater J, Meric-Bernstam F, Hollebecque A, et al. Efficacy and safety of futibatinib in intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions/other rearrangements: subgroup analyses of a phase II study (FOENIX-CCA2). Ann Oncol. 2020;31(suppl 4):S260-S273.
  73. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-2520.
  74. Waterhouse DM, Harvey RD, Hurley P, et al. Early impact of Covid-19 on the conduct of oncology clinical trials and long-term opportunities for transformation: findings from an American Society of Clinical Oncology Survey. JCO Oncol Pract. 2020;16:417-421.
  75. Upadhaya S, Yu JX, Oliva C, Hooton M, Hodge J, Hubbard-Lucey VM. Impact of COVID-19 on oncology clinical trials. Nat Rev Drug Discov. 2020;19:376-377. 
  76. Icon. Adapting clinical trial protocols can help to keep participants enrolled and receiving treatments and assessments. April 2, 2020. www.iconplc.com/insights/blog/2020/04/02/minimise-the-impact-of-covid19-on-clinical-trials-by-considering-in-home-clinical-services. Accessed October 25, 2020.
  77. Saini KS, de Las Heras B, de Castro J, et al. Effect of the COVID-19 pandemic on cancer treatment and research. Lancet Haematol. 2020;7:e432-e435.
  78. US Food and Drug Administration (FDA). Guidance Document. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency Guidance for Industry, Investigators, and Institutional Review Boards. www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency. Updated September 21, 2020. Accessed October 29, 2020.
  79. American Society of Clinical Oncology (ASCO). American Society of Clinical Oncology Position Statement Home Infusion of Anticancer Therapy. June 23, 2020. www.asco.org/sites/new-www.asco.org/files/content-files/advocacy-and-policy/documents/2020_Home-Infusion-Position-Statement.pdf. Accessed September 22, 2020.

Related Items

Accelerated Approval Granted for Infigratinib for the Treatment of Metastatic Cholangiocarcinoma
Web Exclusives
Infigratinib has been approved to treat adults with previously treated locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 fusion or other rearrangement.
Considering Toxicities Associated with Specific and Pan-FGFR Inhibitors
By Jesús Bañales, PhD; Antoine Hollebecque, MD; Milind M. Javle, MD; Angela Lamarca, MD, PhD, MSc
Videos
Drs Javle, Báñales, and Hollebecque describe their thoughts about the use of pan-FGFR inhibitors compared with those that primarily target FGFR2 and the potential of treating CCA with inhibitors of FGFR1, 3, and 4. Moreover, they consider the most common adverse events associated with inhibitors of FGFR2, of which the most difficult to manage are hyperphosphatemia, nail toxicity, eye toxicity, and fatigue. The importance of educating oncologists on how to treat these toxicities is key to maintaining dose intensity of FGFR inhibitors.
The Latest Research in Biliary Tract Cancers Presented at ASCO GI 2021
March 2021, Vol 2, No 1
At the CCA Summit held during the 2021 ASCO Gastrointestinal (GI) Cancers Symposium, Rachna T. Shroff, MD, MS, Chief, Section of GI Medical Oncology, University of Arizona Cancer Center, Tucson, discussed 15 clinical trials that were presented at the ASCO GI Cancers Symposium on cholangiocarcinoma (CCA) and hepatobiliary diseases. She highlighted key advances related to chemotherapy, targeted therapies, and biomarkers in the management of biliary tract cancers, including CCA.
Continuing Progress in Cholangiocarcinoma and Bilary Tract Cancers
By Milind M. Javle, MD
March 2021, Vol 2, No 1
Dear Colleagues, It gives me great pleasure to introduce the March issue of CCA News. Once again, we have several recent developments in cholangiocarcinoma (CCA) clinical research, and these have been reviewed by leaders in the field.
The Role of FGFR Inhibitors in Treating FGFR2 Fusion–Positive Cholangiocarcinoma
By Antoine Hollebecque, MD; Milind M. Javle, MD
Videos
Drs Javle and Hollebecque review the phase 2 clinical trial efficacy data of pemigatinib, infigratinib, and futibatinib as second-line therapy of FGFR2 fusion–positive cholangiocarcinoma, and explore use of these agents in the first-line and adjuvant settings.
Key Cholangiocarcinoma Abstracts Presented at ASCO GI 2021
By Rachna T. Shroff, MD, MS
Videos
Rachna Shroff, MD, from the University of Arizona Cancer Center, presents her insights into important new data in cholangiocarcinoma from ASCO GI 2021. New evidence is being presented on FGFR inhibitors, targeted therapies, chemotherapy in second-line, combination therapy, immunotherapy, and more.
Takeaways from the 2020 Cholangiocarcinoma Summit
By Milind M. Javle, MD
December 2020, Vol 1, No 3
In this last issue for the year, we are highlighting the proceedings of the Second Annual Cholangiocarcinoma (CCA) Summit, which was conducted on October 22-23, 2020. This summit attracted a wide, multidisciplinary audience and was very interactive, despite being a virtual event. An important focus for this meeting was the emergence of molecular targets in CCA and early successes seen with precision medicine in this disease. Many of the key presentations from the summit are included in the current issue and are highlighted below.

Subscribe to CCA News

Stay up to date with personalized medicine by subscribing to recieve the free CCA News print publication or weekly e‑Newsletter.

I'd like to recieve: