HOPA 2019–2020 Publications Committee
Megan Dillaman, PharmD BCOP, Editor
Lisa M. Cordes, PharmD BCOP BCACP, Associate Editor
Christan M. Thomas, PharmD BCOP, Associate Editor
LeAnne Kennedy, PharmD BCOP CPP FHOPA, Board Liaison
Jessica Auten, PharmD BCOP BCPS
Andrea Clarke, PharmD
Jeff Engle, PharmD MS
Sarah E. Hoffman, PharmD BCOP
Sidney V. Keisner, PharmD BCOP
Bonnie A. Labdi, PharmD BCOP
Chung-Shien Lee, PharmD BCOP BCPS
Renee K. McAlister, PharmD BCOP
Heather N. Moore, PharmD BCOP
Jennifer S. Philippon, PharmD candidate
Kendall Shultes, PharmD BCOP
Andrew Tiemann, PharmD candidate
Candice M. Wenzell, PharmD BCOP
Michael J. Williams, PharmD
Board Update: Looking Back, Looking Ahead
Susanne Liewer, PharmD BCOP FHOPA
HOPA President (2019–2020)
Clinical Associate Professor, PGY-2 Oncology Pharmacy Residency Director
University of Nebraska Medical Center College of Pharmacy
The members of HOPA’s board of directors hope you had a restful and enjoyable holiday season full of good times with family and friends, as well as some time to relax after a busy year. At the start of each new year, it is common to reflect on our past endeavors, and 2019 was a busy and productive year for HOPA and our members!
HOPA had many significant accomplishments during the past year. In 2019 our membership increased to more than 3,200! That membership includes pharmacists and technicians who are involved in all phases of oncology pharmacy. It is made up of students; residents; inpatient, outpatient, infusion center, and specialty pharmacists; and those who work in the pharmaceutical industry. HOPA’s diverse membership allows us to provide a variety of educational and professional opportunities, whether a person is just starting out in oncology pharmacy or is a seasoned practitioner.
HOPA’s educational offerings in 2019 were superb! Our annual conference, held in Fort Worth, TX, provided outstanding education for the more than 1,000 members who attended the live conference and those who attended virtually. HOPA also collaborated with the Academy of Managed Care Pharmacy to host a Value in Cancer Care Forum, “Pharmacy’s Call to Action,” in Washington, DC, in June 2019. Experts representing all phases of health care came together to discuss the ever challenging task of defining value in the treatment of cancer. In September, HOPA’s Practice Management program, held in Charlotte, NC, was well attended and provided real-world education for our members who work in the field of pharmacy administration. In addition to our live educational offerings, HOPA continues to provide members with webinars, on-demand education, and opportunities for Board Certified Oncology Pharmacist (BCOP) credit. In 2019 HOPA was proud to offer sessions totaling 38 BCOP credits for members seeking continuing education or advanced clinical education.
HOPA members were incredibly productive in 2019 in various aspects of oncology pharmacy. Whether they were asking questions or sharing their experiences in HOPA’s e-mail discussion groups, completing committee charges, or participating in collaborations with allied organizations, our members were promoting the role of the oncology pharmacist. HOPA, in collaboration with the Oncology Nursing Society (ONS), published the position statement “Ensuring Healthcare Worker Safety When Handling Hazardous Drugs.” HOPA and ONS highlighted the changes in U.S. Pharmacopeia General Chapter 800 and the ways to best protect our members from exposure to hazardous agents. In addition, HOPA also published a Women in Leadership white paper highlighting the challenges that women may face in leadership roles and issuing a call to action to address inequities. We thank each HOPA member who worked on our committees and task forces or served as writers, reviewers, or educational speakers. Your work is inspiring, and your contributions are truly appreciated.
As grateful as we are for HOPA’s remarkable accomplishments in 2019, we are looking ahead to the many things lined up for a wonderful 2020! Our 2020 annual conference will be held in Tampa, FL, and our Annual Conference Committee has an exceptional roster of clinical experts in their fields who are looking forward to sharing their experiences with attendees. In the John G. Kuhn Keynote Lecture, Leigh Boehmer, PharmD BCOP, will share his personal experiences as a survivor of metastatic testicular cancer. We look forward to learning from Dr. Boehmer and our clinical faculty at the conference. In 2020 HOPA will also offer a BCOP Preparatory and Recertification Course for those members wishing to prepare for the BCOP exam or take a review course for their continuing education. HOPA looks forward to continued collaborations with Medscape Oncology to provide oncology education to a broader pharmacy audience. Check out the shared webpage by registering for free at www.medscape.org/sites/advances/hopa. Finally, be on the lookout for our first podcast and the launch of our core competency certificate program. The year ahead promises to be fruitful indeed!
Early Detection Saves Lives: Updates on Cancer Screening
Michelle Nguyen, PharmD BCOP
Clinical Pharmacy Manager, Medical Oncology
New York-Presbyterian Hospital, Columbia University Irving Medical Center
New York, NY
Overall cancer mortality has decreased by 25% from 1990 to 2015 in the United States, which can be attributed to greater awareness of cancer screening in the general population.1 The American Cancer Society (ACS) and the U.S. Preventive Services Task Force (USPSTF) provide cancer screening recommendations each year, with the aim of increasing the likelihood of benefits and limiting the harms from screening. The annual report updates previous recommendations, provides data on cancer screening rates, and discusses issues related to early cancer detection. Through early detection by screening, death rates have been reduced in cancers of the breast, uterine cervix, colon, rectum, prostate, and lung.
Breast Cancer Screening
Female breast cancer death rates have been decreasing since 1989 in the United States through early detection by mammography.2 The goal of screening mammograms is to detect breast cancer early, but this comes with risks because there may be false-positive findings. Providers have debated what age is appropriate for the initiation of a mammography. In 2015, experts offered more guidance on this issue and provided their recommendations in the updated ACS breast cancer screening guidelines. The recommended primary screening exam for average-risk women is an annual mammography starting at age 45. The risk among women aged 40–44 years was lower and more similar to the risk among women in their late 30s, leading the ACS to not make any direct recommendations for screening in this population. Therefore, women aged 40–44 years are encouraged to choose whether to screen earlier than age 45. Women aged 55 or older have the option to transition to biennial screening or continue screening annually. Mammography screening should continue as long as the patient’s overall health is good and life expectancy is 10 years or longer. In addition to the discussion on screening mammograms, breast exams—either self-exams or exams from a medical provider—are no longer recommended by the ACS because research did not show any clear benefit.3
Cervical Cancer Screening
Cervical cancer incidence and mortality rates have markedly decreased over the decades in the United States, with most of the reduction attributed to screening with the Pap test. The number of deaths declined from 2.8 to 2.3 deaths per 100,000 women from 2000 to 2015.4 Vaccination and routine cervical cancer screening are essential in preventing this disease: approximately 70% of human papillomavirus (HPV)–related cancer cases can be prevented with vaccination. The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016 from a three- dose schedule to a two-dose schedule for patients younger than 15 years. The change was prompted after antibody responses for the two-dose schedule were shown to be noninferior to those for young women who received all three doses. In addition, the U.S. Food and Drug Administration approved the use of the HPV vaccine in men and women up to age 45; however, no changes in guidelines have been made, and insurance plans may not cover the vaccine administration after age 26.5
In 2018, the USPSTF updated its recommendation to offer three screening options for women. Women aged 30–65 years may choose the following screening strategies: Pap-only testing every 3 years, high-risk HPV-only testing every 5 years, or co-testing every 5 years. This differs from recommendations by the American College of Obstetricians and Gynecologists and the American Society for Colposcopy and Cervical Pathology for co-testing every 5 years, with alternative options of Pap-only or HPV-only testing every 3 years. The new recommendation by the USPSTF was implemented after its review of randomized and observational studies. It was noted that both co-testing and high-risk HPV testing offer similar cancer detection rates: each prevents one additional cancer per 1,000 women screened as opposed to Pap-only testing.5 The USPSTF continues to recommend triennial cervical cytology for women aged 21 to 29 years.4 The most critical aspect of screening is getting all women screened—regardless of which method is used.
Colorectal Cancer Screening
An accelerated decline in colorectal cancer incidence rates occurred during the past decade, which may be attributed to the increased uptake of screening and removal of precancerous lesions. In the 2018 update, the ACS lowered the age to start screening average-risk people to age 45. This new recommendation was made because of the emergence of new data that showed increasing rates of colorectal cancer in younger populations. The study found that colon and rectal cancer rates had increased by 0.5% to 2% per year from the mid-1990s through 2013 for adults aged 40–54 years. Regular colorectal cancer screening should continue through age 75 if the person is in good health and has a life expectancy of more than 10 years. Different screening options are available, and adults may choose one of the following methods: guaiac-based fecal occult blood test or fecal immunochemical test every year, multitarget stool DNA test every 3 years, flexible sigmoidoscopy every 5 years, colonoscopy every 10 years, or CT colonography every 5 years. For adults older than 85 years, colorectal cancer screening is no longer recommended.6
Prostate Cancer Screening
In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, with a 2.5% lifetime risk of dying. The USPSTF stated in the 2018 update that men aged 55–69 years should decide whether to undergo periodic prostate-specific antigen (PSA) screening for prostate cancer after discussion with their provider. The main difference is the update to the recommendation grade from D in the 2012 USPSTF recommendation to C in the update. The change in recommendation grade is based on additional evidence that increased the USPSTF’s certainty about the reductions in risk of dying of prostate cancer and risk of metastatic disease. Longer-term follow-up of the European Randomized Study of Screening for Prostate Cancer trial found that PSA-based screening for prostate cancer prevents 1.28 men from dying of prostate cancer for every 1,000 men screened. However, men should be advised that screening offers a small potential benefit. Studies continue to demonstrate the harms of PSA-based screening, including false-positive results, overdiagnosis, and overtreatment. The intention of the USPSTF update is to promote the importance of informed decision making prior to screening.7
Lung Cancer Screening
Lung cancer is the leading cause of death from cancer in men and women. This tumor type accounted for an estimated 154,050 deaths in 2018, approximately 26% of all cancer deaths in the United States. Among men, mortality rates have declined by 43% since 1990, and among women, mortality rates have declined by 17% since 2002.2 In the 2013 ACS lung cancer screening guidelines, the recommendation for screening was unclear. Therefore, the ACS clarified this recommendation in the 2017 update by stating that annual screening for lung cancer with low-dose computed tomography (CT) is recommended in adults aged 55–74 years who have a 30 pack/year smoking history and currently smoke or have quit within the past 15 years.2 The USPSTF has a broader age range for lung cancer screening, with recommendations for adults up to age 80 based on modeling studies.8
Adults should recognize the importance of cancer screenings and be reminded when they are due for them. By increasing awareness of regular screening, cancer deaths can continue to decline in the United States.
- Byers T, Wender RC, Jemal A, Baskies AM, Ward EE, Brawley OW. The American Cancer Society challenge goal to reduce US cancer mortality by 50% between 1990 and 2015: results and reflections. CA Cancer J Clin. 2016;66:359-369.
- Smith RA, Andrews KS, Brooks D, et al. Cancer screening in the United States, 2018: a review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin. 2018;68:297-316.
- Oeffinger KC, Fontham ET, Etzioni R, et al.; American Cancer Society. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA. 2015;314:1599-1614.
- U.S. Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. JAMA. 2018;320:674-686.
- Zhang S, Batur P. Human papillomavirus in 2019: an update on cervical cancer prevention and screening guidelines. Cleve Clin J Med. 2019;86:173-178.
- Wolf AMD, Fontham ETH, Church TR, et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018;68:250-281.
- U.S. Preventive Services Task Force, Grossman DC, Curry SJ, et al. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. JAMA. 2018;319:1901-1913.
- Moyer VA, U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160:330-338.
Going Above and Beyond in Your Career Following Residency Training
Megan May, PharmD BCOP
Clinical Oncology Pharmacy Specialist
Baptist Health Lexington
During the time of year when residency candidate interviews are occurring and residency match day is on the horizon, it is only fitting that residents would begin to reflect on their own personal residency experience and the role that postgraduate training has played in shaping who they are today. After being asked to reflect on my own experience as a resident, I knew I needed to start from the beginning of my career journey. By the ripe age of 7, I had established the goal to become a pharmacist when I grew up. My mom had a few female friends who were community pharmacists and who truly enjoyed their career and the quality of life they were able to have while being full-time pharmacists. I started working at a community pharmacy the day I turned 16 in an effort to gain experience in the field. I always knew I wanted to do something that would help others and have a positive impact on their lives. During my first year of pharmacy school, I transitioned my focus to hospital pharmacy and the opportunity to specialize. Throughout my oncology rotation during my postgraduate year-1 residency at UF Health Jacksonville, I fell in love with the positive and encouraging atmosphere of the UF Health Cancer Center. I then went on to complete a postgraduate year-2 (PGY-2) residency in oncology at the Medical University of South Carolina, where I was challenged daily to learn as much as possible and was engulfed in all the oncology opportunities I could find.
The experience and knowledge I gained as a resident was invaluable. Following my residency, I am still using and continuing to build on the education I obtained. I’ve had to learn how to create and implement policies and facilitate practice changes in the clinic, both of which are important skills I use in my practice every day. My year as a resident was one of the more challenging of my career thus far, but it also contained some of the most rewarding experiences. According to the American Society of Health-System Pharmacists, the purpose of a pharmacy residency is “to accelerate the resident’s growth beyond entry-level professional competence in direct patient care and in practice management, and to further develop leadership skills that can be applied in any position and in any practice setting.”1 I can honestly say that this is exactly what my residencies did for me: they put me years ahead of where I would have been professionally without residency training. In pharmacy school you hone critical thinking skills and learn about direct patient care and pharmacotherapy. A residency propelled me above and beyond, allowing me to develop my time management, research design, and professional communication skills, as well as providing opportunities in leadership and public speaking.
After securing a PGY-2 residency, the next phase is to find a job postresidency, and my mentors and preceptors assisted me a great deal during the decision-making process. One of the best pieces of advice I received was to interview at more than one place and keep an open mind. I thought I knew what type of position I wanted and where I wanted to practice; however, that opinion changed during my on-site interviews. I accepted my first postresidency position at Baptist Health Lexington in Lexington, KY, where I remain today. I was one of two oncology specialists hired throughout Baptist Health System in Kentucky, which consists of eight hospitals. I was the first oncology pharmacy specialist at Baptist Health Lexington and was given the opportunity to develop my own position in the Cancer Center’s medical oncology clinic, gynecologic oncology clinic, and outpatient infusion center. The majority of my time is spent in the outpatient clinic and infusion center; however, I am the liaison between the pharmacy department and the inpatient oncology unit. In our medical oncology clinic and gynecological cancer clinic, we average approximately 100 outpatient visits per day, and in the infusion center we average about 63 patient infusion visits per day. We treat both benign and malignant hematology, oncology, and gynecological cancers. Because we care for patients with a variety of disease states on any given day, each day brings something new.
The most satisfying part of my job is my interaction with patients. I get to know my patients personally during their journey fighting cancer, which allows me to better serve them on an individual basis. Our patients are grateful for everything we do, and they express that gratitude to the entire staff. I have also had the opportunity to initiate the expansion of pharmacy services in the clinics by becoming a readily available resource for the entire staff. Over time, I have become even more involved with the education of our patients and now have separate appointments with patients to discuss their cancer treatment and what to expect throughout their treatment process.
Over the last 6 years, my role has changed numerous times in order to fulfill the needs of our clinic and the patients we serve. My residency training provided me the necessary tools and skills to establish innovative programs and incorporate pharmacy services throughout the Cancer Center. I developed oncology competencies for the staff pharmacists to ensure that they were proficient in the oncology area; I presented monthly education sessions with formal lectures, gave updates on recent publications, and created annual competency assessments. At one time I was also responsible for developing annual competencies in compounding hazardous medications and tracking completion of this competency by staff pharmacists and technicians. After practicing for 4 years, I was able to show the value of having a PGY-2-trained oncology pharmacist on staff and completed a research project that demonstrated the need for a second pharmacy position in the Cancer Center to focus on patients receiving oral chemotherapy agents. On the basis of the project data, positions were created for a full-time PGY-2 trained oncology pharmacist and an oral chemotherapy financial navigator. After successfully hiring a financial navigator for patients receiving oral chemotherapy, the team and I were able to facilitate the creation of another new position for a financial navigator focusing on patients receiving intravenous medications.
In April 2019, I had the honor and privilege of accepting the HOPA New Practitioner Award at HOPA Ahead. The HOPA New Practitioner Award is given to an early-career practitioner who has made a significant contribution to developing or supporting clinical hematology/oncology pharmacy services. It is wonderful to know that I was nominated for this award by my current partner at work, a mentor of mine, and one of my past students, and I am humbled to have been chosen by the committee. Residency training set me up to be able to better serve my patients and community, even as a new practitioner. Residency also provided a framework that continues to be valuable as I seek to be an educator to other pharmacists and learners.
Oncology pharmacists are expanding their roles in both the clinic and inpatient settings. As more providers realize the benefits of having a pharmacist working directly with them, they are requesting that a pharmacist join their team. I am still a newer practitioner, but in the 6 years I have been in practice, I have noticed that both nurses and providers rely on me to provide education to staff and patients and provide consultation on difficult patient cases. In some states, pharmacists can provide collaborative services to help reduce the medical practitioner’s time and add value to the care of the cancer patient. Pharmacists are starting their own provider clinics to deliver supportive care management, patient instruction on oral chemotherapy (especially adherence), and education on many other aspects of cancer care. Our responsibilities and privileges will only increase as we promote our abilities and as our potential is realized by the providers we work with.
I believe that pharmacist-run clinics will continue to increase in number and expand in scope. Pharmacists provide a unique perspective for the patient and often incorporate specialized education, specialized knowledge about medicine, and information about cost into their treatment decisions. Looking back, I see that one of the biggest strengths of completing a PGY-2 oncology residency was the initial establishment of a professional network that continues to grow. It allows me to learn about the different roles oncology pharmacists are playing in clinics and infusion centers and bring suggestions back to my hospital for improvements in practice integration. Residency training advanced my skills and continues to give me opportunities for future advancement by teaching me how to navigate this complex healthcare system. As the American historian Daniel J. Boorstin said, “Education is learning what you didn’t even know you didn’t know.”
- American Society of Health-System Pharmacists. Accreditation standards for PGY1 pharmacy residencies. Available at https://www.ashp.org/Professional-Development/Residency-Information/Residency-Program-Directors/Residency-Accreditation/Accreditation-Standards-for-PGY1-Pharmacy-Residencies. Accessed December 26, 2019.
Working to Keep the Lights On in the Era of High-Cost Antineoplastic Treatment: Strategies for Managing Inpatient Drug Administration
Zahra Mahmoudjafari, PharmD BCOP DPLA
Clinical Pharmacy Manager—Hematology, Bone Marrow Transplant, Cellular Therapeutics
University of Kansas Health System
Kansas City, KS
The cost of cancer care has never been higher, and as the U.S. Food and Drug Administration (FDA) continues to approve new drugs, those costs climb higher still. Between August 2018 and July 2019, the FDA approved 17 new antineoplastic therapies.1 The costs associated with adult cancer treatment in the United States continue to be significant, totaling approximately $87.2 billion in 2012.2 New targeted antineoplastic agents are priced at $6,000–$12,000 per month, or approximately $70,000–$140,000 annually, with immunotherapy costs even higher.3 Drug acquisition costs are the biggest source of spending in the pharmacy department and can account for approximately 80% of the total budget.4 Under a diagnosis-related group payment structure and with these new approvals, total inpatient drug spending is increasing and contributing to rising total hospital expenditures. Independent of the increasing cost of treatment, institutions are working with higher operating costs and changing reimbursement models while also being challenged to provide high-quality, consistent patient care at the lowest possible expense.5
Given these staggering statistics, it is imperative to implement cost-saving strategies, maximize reimbursement through use of drug discounts (i.e., federal 340B outpatient drug discount pricing) and avoid diagnosis-related group inpatient reimbursement.6 The American Society of Health-System Pharmacists has recommended guidelines for medication management strategies that cover three areas:7 pharmacy-directed activities, such as purchasing, inventory management, and waste reduction interdisciplinary activities reimbursement and charging strategies.
A survey of 281 cancer institutions confirmed that one strategy includes administering antineoplastic treatment in the outpatient clinic setting. A growing number of published articles on the implementation of such changes by single institutions document the achievement of remarkable cost savings. One study described the implementation of a policy limiting inpatient administration of antineoplastic medication that resulted in decreased numbers of inpatient admissions and associated drug cost savings of approximately $160,000 annually.8 Another report demonstrated drug cost savings of nearly $2 million and a cumulative cost savings for a health system of approximately $3.3 million in a 2-year period.9 Shifting the administration of these agents to the outpatient setting benefits both the treating institution and the patient because of pricing structures.
Another cost-saving strategy includes the use of Pharmacy and Therapeutics (P&T) committees to restrict medication usage to specific areas of administration, specialties, or patient populations. One report described the development of a standardized review process with a request form for the use of outpatient-restricted medications.10 Another institution developed a High-Cost Medication Review Committee, describing a standard process for inpatient high-cost medication approval. This committee was composed of a multidisciplinary team that reviewed inpatient requests based on clinical efficacy and appropriateness, with an expectation that a decision is made within 48 hours. Through the establishment of the review committee, the institution reported a cost savings of approximately $490,000 annually.11
At our institution, we have implemented a number of these strategies. For example, we routinely transition our chemotherapy regimens to the outpatient setting. Complex hematologic regimens such as R-ICE, R-EPOCH, HyperCVAD, and HIDAC are routinely administered in the outpatient setting. We consistently administer both autologous and allogeneic preparative regimens in the outpatient setting. Our approach has been successful because we have clear guidelines for patients who are receiving outpatient administration, including adequate patient caregiver support, requirements for proximity to the outpatient infusion center, and a triage line that is available for questions and support. Our outpatient infusion clinic is open 7 days a week and is open until 7 pm on weekdays and 2 pm on weekends. We also use tools such as ambulatory infusion pumps and have in place policies regarding approved line access for outpatient administration of chemotherapy via an ambulatory pump.
Formulary management is a key element to our cost-containing strategy. Our Hematology/Oncology/Bone Marrow Transplant (H/O/BMT) P&T Subcommittee, a multidisciplinary team with hematologists and oncologists serving as voting members, reviews all new drug approvals for clinical efficacy while also evaluating them for cost. Our formulary categorizations include addition to formulary without restriction addition to formulary with restrictions nonformulary not stocked nonformulary not allowed.
This formulary status is reflected in our electronic medical record for medications that are restricted to use in the outpatient setting; a best-practice advisory alert appears upon the entry of outpatient restricted medications. When a medication has been categorized as high cost or restricted to outpatients, we note this on the maintained list that is readily accessible to our team.
If a medication that is restricted to outpatient administration is requested in the inpatient setting, our clinical pharmacist enters the request through an electronic High-Cost Log. Information required in the request includes indication, literature supporting use, potential alternative therapies, and the reason for inpatient administration. This log electronically notifies the cancer care leadership team of the request. The administrator then sends a request, including information about the patient’s case and supporting literature, to the H/O/BMT P&T Subcommittee for a vote within 48 hours. If the request is approved by the subcommittee, the administrator approves the electronic log request, thereby notifying our supply chain team to order the medication. After the medication has been ordered, the supply chain team updates the electronic request, and this is communicated to the clinical team pharmacist. This log must be used each time a dose is requested. If the request is denied, the requesting provider is notified, and the patient does not receive the requested medication as an inpatient. This log was initiated in January 2019 and has been used to process 228 requests in the first 11 months following its initiation. The log has also been instrumental in tracking trends and has resulted in the creation of an approved utilization policy for rituximab. In addition, this approach allows our purchasing team to maintain the minimum amount of stock of these high-cost therapies, making us good stewards of the pharmacy budget.
Engagement of our physician colleagues through our H/O/BMT P&T Subcommittee has been essential to our success. By using evidence-based studies and drug assessment data to review each new medication, we define our utilization up front. We routinely report back and discuss methods for cost reduction, supported by evidence-based research, to propose changes. We also identify physician champions for specific initiatives. Despite these electronic standardizations, the success of our high-cost management program is owed in large part to the activities of our clinical pharmacy team. Their active daily involvement and enforcement of the guidelines has been crucial to the success of these efforts.
By using the outpatient administration process outlined above, formulary management, technological tools, and partnership with the multidisciplinary team, we minimize cost to the institution while continuing to deliver consistent and high-quality patient care. Each of these strategies, if implemented, can be helpful to other institutions seeking to minimize their overall inpatient drug costs.
- American Association for Cancer Research. AACR Cancer Progress Report 2019. Available at https://www.cancerprogressreport.org/Documents/AACR_CPR_2019.pdf. Accessed November 27, 2019.
- Soni A. Top five most costly conditions among adults age 18 and older, 2012: estimates for the U.S. civilian non-institutionalized population. Statistical Brief #471. Agency for Healthcare Research and Quality. April 2015. Available at www.meps.ahrq.gov/mepsweb/data_files/publications/st471/stat471.pdf. Accessed November 27, 2019.
- Kantarjian HM, Fojo T, Mathisen M, Zwelling LA. Cancer drugs in the United States: justum pretium—the just price. J Clin Oncol. 2013;31:3600-3604.
- NORC at the University of Chicago. Trends in hospital inpatient drug costs: issues and challenges. Final report. October 11, 2016. Available at www.aha.org/content/16/aha-fah-rx-report.pdf. Accessed November 27, 2019.
- Barr TR, Towle EL. Oncology practice trends from the National Practice Benchmark. J Oncol Pract. 2014;10:407-410.
- Warren A, Shankar A. Oncology transactions and the 340B drug pricing program. J Oncol Pract. 2013;9:89–91.
- ASHP Expert Panel on Medication Cost Management. ASHP guidelines on medication cost management strategies for hospitals and health systems. Am J Health-Syst Pharm. 2008;65:1368-1384.
- Foster AE, Reeves DJ. Inpatient antineoplastic medication administration and associated drug costs: Institution of a hospital policy limiting inpatient administration. P T. 2017;42:388-393.
- McBride A, Campen CJ, Camamo J, et al. Implementation of a pharmacy-managed program for the transition of chemotherapy to the outpatient setting. Am J Health Syst Pharm. 2018;75:e246-e258.
- Lau KM, Derry K, Dalton A, Martino J. Outcomes of inpatient administration of restricted antineoplastic medications at a large academic medical institution. P T. 2019;44:481-485.
- Durvasula R, Kelly J, Schleyer A, Anawalt BD, Somani S, Dellit TH. Standardized review and approval process for high-cost medication use promotes value-based care in a large academic medical system. Am Health Drug Benefits. 2018;11:65-73.
Pharmacists’ Influence on Immunization in Cancer Patients: Increasing Vaccination Rates and Reducing Mortality from Preventable Diseases
Heidi D. Finnes, PharmD BCOP
Member of HOPA’s Quality Oversight Committee
Senior Manager, Pharmacy Cancer Research
Assistant Professor of Pharmacy
Mayo Clinic Cancer Center
Immunizations prevent approximately 2–3 million deaths each year and have proven to be a safe and cost effective use of healthcare dollars.1 Measured in light of the federal government’s Healthy People 2020 goals, vaccination rates among adults and children are still substandard.2 As trusted and accessible members of the healthcare profession, pharmacists play a key role in heightening patients’ participation in immunizations.3 A meta-analysis by Isenor and colleagues found that patient vaccination rates increased when pharmacists were involved in the immunization process in any capacity: as patient educators, as facilitators of others in the delivery of vaccines to patients, and as administrators of vaccines in the pharmacy.4 Every state in the United States now allows for pharmacist-provided immunization in some capacity.5 The types of vaccinations allowed and the age of patients that pharmacists can vaccinate differ based on state regulations. HOPA’s Quality Oversight Committee, of which I am a member, would like to highlight some successes and potential areas of development for hematology/oncology pharmacists in meeting this essential quality metric for patients with cancer.
Less than 50% of patients undergoing cancer treatment receive the recommended seasonal influenza vaccine.6 Studies have shown varying results in patients’ ability to mount serologic responses to influenza vaccinations while they are receiving chemotherapy. A recent population-based study of more than 26,000 Canadian patients with cancer who underwent influenza testing found the influenza vaccine to be effective.7 Immunization was associated with reduced hospitalization in patients with laboratory-confirmed influenza. Vaccine effectiveness was higher in patients with solid-tumor versus hematologic malignancies (25% vs. 8%, p = .015). No difference was found in influenza vaccine efficacy in patients receiving chemotherapy versus those who were not receiving therapy (14% vs. 22%, p = .38).7 Because this trial increased the evidence of influenza vaccine effectiveness in patients with cancer, it is important to identify opportunities to improve vaccination rates. A quality improvement project at Massachusetts General Hospital Cancer Center sought to better a 40% influenza vaccination rate in patients receiving parenteral antineoplastic therapy in its clinic.8 During a 1-month period, with the oversight of board-certified oncology pharmacists, pharmacy students reviewed the immunization history of 617 patients who were receiving parenteral chemotherapy. One hundred twenty-four patients were interviewed to verify their influenza vaccination status, and 33 patients received the vaccine. With the effort of pharmacists-in-training, influenza vaccination rates at Massachusetts General Hospital Cancer Center increased to 60.5%.8
Post-Hematopoietic Cell Transplant Revaccination
Hematopoietic cell transplant (HCT) patients 6–24 months post-transplant should be immunized against pathogens such as pneumococcus, Haemophilus influenza, Herpes zoster, meningococcus, hepatitis A and B, diphtheria/tetanus toxoids and acellular pertussis, polio, and measles-mumps-rubella.9 Hematology/oncology pharmacists play a critical role in ensuring that appropriate vaccination schedules are maintained, with consideration of clinical factors such as active graft-versus-host disease, use of immunosuppressive therapies, and recent administration of chemotherapy or B-cell-depleting treatments.10 A pharmacist-directed quality improvement pilot project to standardize the timing of HCT vaccinations post-transplant was conducted at Saint Luke’s Mountain States Tumor Institute in Boise, ID. Over a 4-month period, a total of 12 patients were given 64 post-transplant vaccinations by an immunization-certified pharmacist. Providers expressed satisfaction with the pharmacy service, and patients experienced shorter wait times and an overall improvement in care. Pharmacists’ involvement in this vaccination clinic also decreased potential immunization errors and omissions for HCT patients.11
Human Papillomavirus (HPV) Vaccination
HPV is a sexually transmitted infection that results in approximately 44,000 new cases of HPV-associated cancers (cervical, oropharyngeal, and penile cancers) each year.12 Common types of HPV (strains 16 and 18) can be prevented with immunization prior to sexual activity. The Advisory Committee on Immunization Practices recommends that the three-dose HPV vaccination series be routinely recommended at age 11 or 12 years.13 Data from the 2018 National Immunization Survey—Teen, a report on more than 18,000 adolescents, showed that only 50% of youth have received the HPV vaccine series. Sixty-eight percent of adolescents received one or more HPV vaccine doses.14 These survey numbers are well below the Healthy People 2020 goal of 80% HPV vaccination for teens.2 Pharmacist-led vaccine clinics are an innovative way to increase HPV immunization and reduce the incidence of HPV-associated cancers. Many states, however, allow pharmacists’ administration of HPV vaccines only in adult women ages 18 or older. Some states require a physician-specific collaborative practice agreement with the pharmacist, or an HPV vaccine prescription, in order for patients to be vaccinated.15 Although laws about HPV administration currently vary among states, survey results show that 79% of physicians and 81% of parents approve of pharmacist-guided HPV vaccinations.16 A pilot of pharmacy-located HPV vaccination clinics was recently conducted at pharmacies in North Carolina, Michigan, Iowa, Kentucky, and Oregon. Barriers to expansion of this pharmacy vaccination program included third-party billing reimbursement practices and clinics’ limited affiliation with primary care and specialty clinics (and therefore a decrease in the number of referrals for vaccination).17 Opportunity exists for hematology/oncology pharmacists to increase legislators’ and the public’s awareness of pharmacist-provided HPV vaccination services for this preventable disease.
Nationally, vaccination rates continue to be a high-priority quality metric among multiple stakeholders, including public health, payer, and medical organizations. Improvements in these metrics are dependent on changes at local practice sites and organizations led by individuals who are responsible for clinical operations and are providing direct care for patients. Pharmacists and pharmacists-in-training are in a prime position to make a substantial impact in these metrics at local practices and organizations. By receiving appropriate vaccination training, augmenting documentation of vaccine doses in the electronic health record, and collaborating with local providers and clinics, pharmacists can contribute significantly to thwarting preventable infections and cancers.
- World Health Organization (WHO). Immunization. Available at https://www.who.int/topics/immunization/en/. Accessed December 2, 2019.
- Centers for Disease Control and Prevention. Division for Heart Disease and Stroke Prevention. Healthy People 2020. Washington, DC. Available at https://www.cdc.gov/dhdsp/hp2020.htm. Accessed December 2, 2019.
- American Society of Health-System Pharmacists Council on Professional Affairs. ASHP guidelines on the pharmacist’s role in immunization. Am J Health Syst Pharm. 2003;60:1371-1377.
- Isenor JE, Edwards NT, Alia TA, et al. Impact of pharmacists as immunizers on vaccination rates: a systematic review and meta-analysis. Vaccine. 2016;34:5708-5723.
- Immunization Action Coalition. State Information. States Authorizing Pharmacists to Vaccinate. Available at https://www.immunize.org/laws/pharm.asp. Accessed December 2, 2019.
- Loulergue P, Mir O, Alexandre J, et al. Low influenza vaccination rate among patients receiving chemotherapy for cancer. Ann Oncol. 2008;19:1658.
- Blanchette PS, Chung H, Pritchard KI, et al. Influenza vaccine effectiveness among patients with cancer: a population-based study using health administrative and laboratory testing data from Ontario, Canada. J Clin Oncol. 2019;37:2795-2804.
- Kim EB, Zangardi M, Rostamnjad L, et al. Impact of a student pharmacist-directed pilot intervention on influenza vaccination documentation and administration rates in older adults receiving parenteral anticancer therapy. J Clin Oncol. 2019;37(27_suppl):abstract 71.
- Centers for Disease Control and Prevention. Vaccine Recommendations and Guidelines of the ACIP [Advisory Committee on Immunization Practices]. Available at https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html. Accessed December 2, 2019.
- Clemmons AB, Alexander M, DeGregory K, et al. The hematopoietic cell transplant pharmacist: roles, responsibilities, and recommendations from the ASBMT Pharmacy Special Interest Group. Biol Blood Marrow Transplant. 2018;24:914-922.
- Pence S, Mancini R. Pharmacist-run vaccination and medication management service for patients after bone marrow transplant. J Hematol Oncol Pharm. 2015;5:8-11.
- Centers for Disease Control and Prevention. HPV and Cancer. Available at https://www.cdc.gov/cancer/hpv/index.htm. Accessed December 2, 2019.
- Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.
- Walker TY, Elam-Evans LD, Yankey D, et al. National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years—United States, 2018. MMWR Morb Mortal Wkly Rep. 2019;68:718-723.
- Brewer NT, Chung JK, Baker HM, et al. Pharmacist authority to provide HPV vaccine: novel partners in cervical cancer prevention. Gynecol Oncol. 2014;132:S3-8.
- Shah PD, Calo WA, Marciniak MW, et al. Support for pharmacist-provided HPV vaccination: national surveys of US physicians and parents. Cancer Epidemiol Biomarkers Prev. 2018;27:970-978.
- Calo WA, Shah PD, Gilkey MB, et al. Implementing pharmacy-located HPV vaccination: findings from pilot projects in five U.S. states. Hum Vaccin Immunother. 2019;15:1831-1838.
Selinexor: A Nuclear Export Inhibitor for Treating Relapsed or Refractory Multiple Myeloma
Sara Moran Smith, PharmD BCOP
Oncology Clinical Pharmacist
M Health Fairview Maple Grove Cancer Center
Maple Grove, MN
Despite significant advances in therapy for multiple myeloma (MM) in recent years, it continues to be an incurable hematologic malignancy. MM primarily affects the elderly, with a median age of diagnosis of 69 and an estimate of 32,000 new diagnoses in 2019.1 MM is characterized by uncontrolled proliferation of clonal plasma cells. Treatment generally includes an induction regimen, autologous transplant for eligible patients, and maintenance therapy. Although transplant gives patients the best chance for overall survival, all patients are expected ultimately to relapse. In the relapse setting, agents include proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory agents (thalidomide, lenalidomide, pomalidomide), alkylating agents (cyclophosphamide, bendamustine), and/or monoclonal antibodies (daratumumab, elotuzumab).1,2 Daratumumab is an anti-CD38 monoclonal antibody approved for use in newly diagnosed patients and relapsed or refractory patients.3 Elotuzumab is a SLAMF7-directed monoclonal antibody approved for use in the relapsed setting.4 Despite these treatments, development of resistance continues.
A cell has various proteins moving in and out of the nucleus to and from the cytoplasm. Exportin-1 (XPO-1) is a karyopherin, a family of proteins that transport molecules between the nucleus and cytoplasm.5,6 In normal cells, XPO-1 is essential in maintaining homeostatic levels of proteins and messenger RNAs (mRNAs).6 These proteins include tumor suppressor proteins (TSPs) and oncogenic mRNAs. Overexpression of XPO-1 in cancer cells inactivates TSPs by excluding them from the nucleus.6 In addition, this overexpression leads to increased transport of oncogenic mRNAs to the cytoplasm where translation and oncogenic protein production occurs.7 XPO-1 is highly expressed in patients with MM, particularly in patients resistant to bortezomib.8 Furthermore, high expression of XPO-1 is associated with a poor prognosis.8
Selinexor (Xpovio) is an oral small-molecule nuclear export inhibitor that targets XPO-1 and is approved for use in patients who have received at least two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody.9 Selinexor inhibits XPO-mediated nuclear export of TSPs and oncogenic mRNAs, resulting in G1/G2 arrest and apoptosis.10
Selinexor received accelerated approval in combination with dexamethasone following its evaluation in the STORM trial. STORM was a multicenter single-arm open-label study of patients with relapsed or refractory MM. STORM part 2 included 122 patients who had previously received three or more antimyeloma treatment regimens. Patients who were enrolled had to be documented as refractory (not intolerable) to at least three treatment regimens—including an alkylating agent, glucocorticoids, bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab—and to their last line of therapy.9 Of the 122 patients, 83 patients had relapsed or refractory MM that was documented as being refractory to bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab.9 These patients were dosed with selinexor 80 mg and dexamethasone 20 mg on days 1 and 3 of each week.9,11 The major efficacy outcome was overall response rate (ORR). The accelerated approval granted for selinexor was based on this prespecified subgroup of 83 patients who were documented as pentarefractory because the benefit-risk ratio appeared greater in this more heavily pretreated population compared to the overall trial population.9 Median time to first response was 4 weeks, and median duration of treatment was nearly 4 months.9,11
Many people in the relapsed or refractory MM population struggle with side effects from previous therapy, particularly peripheral neuropathy. Selinexor is not associated with any peripheral neuropathy, making it a particularly attractive option for these patients. Selinexor does have side effects that can be managed with dose reductions and supportive therapies.
The overall incidence of nausea was 72%, with 10% of patients experiencing grade 3 or 4 nausea.9,11 It is important to take prophylactic measures with a 5-HT3 antagonist because the median time of onset for nausea is 3 days, and for vomiting, 5 days.9 If nausea continues, an additional antinausea agent should be added, such as an NK-1 receptor antagonist like rolapitant. Fosaprepitant and aprepitant should be avoided, given the significant interaction with high-dose dexamethasone, which can cause additional side effects, including hyperglycemia and edema. Another successful antinausea agent is olanzapine, an atypical antipsychotic, which can be initiated at low doses, 2.5–5 mg daily, and can be increased to up to 10 mg daily. If patients experience grade 3 nausea despite these interventions, the dose should be interrupted and the medication restarted at the next dose level after nausea has decreased to grade 1 or better.9
Thrombocytopenia is a common side effect of selinexor used in relapsed or refractory MM patients. Any-grade thrombocytopenia was 74%, with 61% of those patients having grade 3 or 4.9,11 Median time to onset is 22 days, with bleeding occurring in 23% of patients.9,11 Platelet counts should be monitored at baseline and throughout therapy. If the platelet count drops to <75,000/mcL, selinexor should be reduced by one dose level. If bleeding is present, selinexor should be withheld and restarted at the next dose level.9 Many MM patients starting therapy may have grade 2 or higher thrombocytopenia due to their disease. It’s important to distinguish these patients from the cases addressed in the dose-modification guidelines. Dose modifications contained in the package insert pertain to platelet counts while the patient is on therapy, not at the start of therapy. Any patient who starts treatment with a platelet count of <75,000/mcL should begin treatment at the full dose to receive the maximum benefit. Before dose modifications are made for patients with a low platelet count while on therapy, a conversation about risk versus benefit and the extent of the patient’s disease should be held with the oncologist.
An atypical side effect of this oral targeted agent is hyponatremia. Median time to onset is 8 days; thus it is important to monitor sodium levels at baseline and during treatment. It is important to correct sodium levels for concurrent hyperglycemia.9 Hyponatremia should be treated per institutional guidelines. Some patients may benefit from taking 1 gram of sodium three times per day to maintain appropriate sodium levels while they are on therapy.
Other reported side effects (all grades) include fatigue (73%), anemia (59%), anorexia (53%), weight decrease (47%), diarrhea (44%), constipation (25%), and upper respiratory tract infections (21%).9
The rate of treatment discontinuation because of adverse events was 27%.9 Fifty-three percent of patients had a reduction in selinexor dose, and 65% had a dose interruption.9 It is therefore common for patients to require a dose reduction or interruption (or both) while on therapy. It is important to note, however, that patients benefit most from therapy when they start at the full dose. Because their disease is pentarefractory and is progressing rapidly, full doses of selinexor will provide the best chance for the patient to achieve a response. If the patient experiences side effects, the dose can be adjusted for better tolerability.
Currently, no drug interactions have been reported with selinexor.
How Xpovio Is Supplied
Xpovio comes in dose packs for each dose level.9 The starting dose is 80 mg twice weekly. The first dose reduction is 100 mg weekly, the second reduction is 80 mg weekly, and the last recommended dose reduction is 60 mg weekly.9 Further dose reductions are not recommended because patients would likely not benefit from therapy. All dose packs contain 20-mg tablets. Therefore, if a patient starts on a full dose of 80 mg twice weekly and requires a dose reduction, the patient can continue to use the current dose pack with instructions of how many 20-mg tablets to take before getting a new dose pack of 100-mg dosed weekly.
Selinexor is currently undergoing clinical trials for use in a number of other disease states, including gastrointestinal stromal tumor, soft tissue sarcomas, non-small-cell lung cancer, non-Hodgkin lymphoma, acute myeloid leukemia, breast cancer, diffuse large B-cell lymphoma, and a number of other malignancies.12
Sara Moran Smith is a speaker for Karyopharm Therapeutics.
- Peterson TJ, Orozco J, Buege M. Selinexor: a first-in-class nuclear export inhibitor for management of multiply relapsed multiple myeloma. Ann Pharmacother. December 2, 2019. doi:10.1177/1060028019892643. [Epub ahead of print]
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 2.2020 (October 9, 2019). Available at https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed December 8, 2019.
- Darzalex [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2019.
- Empliciti [package insert]. Princeton, NJ: Bristol-Myers Squibb Co.; 2015.
- Das A, Wei G, Parikh K, Liu D. Selective inhibitors of nuclear export (SINE) in hematological malignancies. Exp Hematol Oncol. 2015;4:7.
- Sun Q, Chen X, Zhou Q, Burstein E, Yang S, Jia D. Inhibiting cancer cell hallmark features through nuclear export inhibition. Signal Transduct Target Ther. 2016;1:16010.
- Culjkovic-Kraljacic B, Borden KL. Aiding and abetting cancer: mRNA export and the nuclear pore. Trends Cell Biol. 2013;23:328-335.
- Tai YT, Landesman Y, Acharya C, et al. CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications. Leukemia. 2014; 28(1):155-165.
- Xpovio [package insert]. Newton, MA: Karyopharm Therapeutics Inc.; 2019
- Gandhi UH, Senapedis W, Baloglu E, et al. Clinical implications of targeting XPO1-mediated nuclear export in multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018;18:335-345.
- Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381:727-738.
- U.S. National Library of Medicine. ClinicalTrials.gov. Available at https://www.clinicaltrials.gov/. Accessed December 8, 2019.
Pharmacy Residents’ Mental Wellness: Why and How to Prioritize Resilience in Residency
Kala Rorabaugh, PharmD BCPPS
Pharmacy Clinical Specialist, Pediatric Hematology/Oncology
WVU Medicine J. W. Ruby Memorial Hospital
Aaron Stewart, PharmD CTTS
Postgraduate Year-2 Oncology Pharmacy Resident
WVU Medicine J. W. Ruby Memorial Hospital
Spencer Yingling, PharmD
Postgraduate Year-2 Oncology Pharmacy Resident
WVU Medicine J. W. Ruby Memorial Hospital
In recent years, discussions about the overall wellness of healthcare providers and the effect that it may have on patient care have dominated national professional organizations.1 Although burnout among healthcare providers, including pharmacists, is not a new phenomenon, minimal guidance on promoting wellness has been given to new pharmacists to help them prevent burnout throughout a career.
The term burnout was coined in 1974 by H. J. Freudenberger to describe the effects of long-term exhaustive stress associated with one’s occupation.2 The characteristics include visible exhaustion and fatigue, sleeplessness, frustration, paranoia about one’s colleagues, and inflexibility. In 2019, the World Health Organization (WHO) announced that burnout would be updated in the International Classification of Diseases (ICD-11) in 2022 to a syndrome “characterized by feelings of energy depletion or exhaustion, increased mental distance from one’s job, or feelings of negativism or cynicism related to one’s job, and reduced professional efficacy.”3 Similar to Freudenberger, WHO recognizes the correlation between prolonged occupational stress and burnout.
Le and Young evaluated the stress experienced by pharmacy residents using a questionnaire that included the 10-item Perceived Stress Score (PSS10) and the Multiple Affect Adjective Checklist–Revised (MAACL-R).4 The PSS10 is a validated tool used to evaluate perceived stress on a scale of 0 to 40, where higher scores correlate with higher perceived stress levels. The MAACL-R is a licensed test used to evaluate the “affect of individuals; specifically depression, anxiety, hostility, and dysphoria.” The PSS10 results showed a mean ±SD perceived stress level of 19 ± 5.90 and a statistically significant correlation between elevated PSS10 scores and a work week longer than 60 hours. According to the MAACL-R results, working more than 60 hours per week was also statistically significantly correlated with depression, hostility, and dysphoria. Elevated PSS10 scores were correlated with statistical significance in relation to anxiety, depression, hostility, and dysphoria.
The increased stress on pharmacy residents can have serious adverse effects on both residents and patients. In the United States, depression affects about 7% of the general population but affects 30% of medical residents.5,6 Although the data on pharmacy residents do not yet exist, given their strenuous training, it is likely that they also have an increased incidence of depression. In 2004, the aggregate suicide rate ratio among male and female physicians compared to the general population was 1.41 (95% confidence interval [CI], 1.21–1.65) and 2.27 (95% CI, 1.90–2.73), respectively.7 Reports of medical resident suicides are regrettably easy to find, and in 2011, a pharmacy resident in South Carolina took her own life.8 Despite the obvious negative impact on the individual resident, patients are also potentially at risk. Le and Young evaluated the relationship between pharmacy residents’ stress and medication errors.9 Residents were asked to respond to the PSS10 and self-report medication errors. Perceived stress scores were positively correlated with self-reported medication errors (p < .001) among all residents surveyed.
At West Virginia University (WVU) Medicine, a Pharmacy Residency Wellness Program was designed to educate residents about wellness, provide them with the tools to help combat burnout, and remove the stigma associated with mental illness. The program began as a small session hosted by two preceptors, in which the preceptors provided anecdotes about their own experiences as well as tools they used to cope with stress. The program was expanded after residents gave positive feedback.
The first formal session was an introduction to the wellness program that included the reasons for implementing the program (outlined above), along with important information about WVU Medicine’s Employee Assistance Program, mental health resources in the community, and stories of preceptors’ personal experiences, all of which helped to remove the stigma associated with mental illness.
The director of the SupportingYOU Second Victim program at WVU Medicine Children’s Hospital spoke with the residents and preceptors about that program. WVU Health Sciences Building Wellness Center staff provided presentations by a neuroscientist, a clinical therapist, and a yoga instructor, who educated residents and preceptors on mindfulness and meditation, covering the scientific evidence for practicing meditation and instruction on yoga poses; a meditation session was also included. The clinical therapist discussed different types of mental health care, mental illness stereotyping, and the physiological responses to stress. Three preceptors collaborated to create an activity to help residents name their values and target their actions to match those values, both at work and at home. Members from the pediatric supportive care team discussed death and dying with the residents and preceptors. Future sessions will cover exercise, faith, sleep hygiene, financial health, and career transitions. We are incredibly lucky to have the support from our leadership and department to develop and maintain a wellness program.
Wellness Tips from the Pharmacy Residency Mentorship and Wellness Coordinator
Know what tools are available and reach out. Seek out employee assistance programs or local mental health offices. Do not be afraid to set up a baseline appointment with a therapist; an advantage is that after you become an established patient, it will be easier for you to schedule future appointments. The National Suicide Prevention Lifeline number is 1.800.273.8255, and the Crisis Text Line can be contacted by texting CONNECT to 741741.5
Develop coping skills. Maintain work-life balance, and do not be afraid to set boundaries where necessary. Maintain social connections by reaching out to friends and family members or by building new relationships. Learn positive coping skills from mentors.
Manage your time well. Managing your time can help reduce stress. Knowing first what your weaknesses are and then addressing what may hold you back can help propel you forward. Make a priority list instead of a to-do list. Break those priorities into bite-size pieces. For example: “Review 5 patient charts” does not seem as daunting as “Conduct research.”10 Avoid social media: not only does it derail productivity, but in 2014, Vogel and colleagues found a negative correlation between time spent on Facebook and self-esteem, especially when one is viewing people whose lives seem better than that of the study subject.11
Advocate for mental health care. Be an advocate for mental health care within your health system.
Wellness Tips from Oncology Residents
The idea that high stress levels are expected and should be tolerated throughout residency exists throughout the healthcare community. The implementation of the wellness program at our institution has helped correct that erroneous idea. Our key takeaways are these:
Don’t wait for mental health concerns to arise before seeking help. Feeling stressed and inadequate are common experiences for residents and are no less important than the residency program itself. Early recognition of these concerns is important and can help residents obtain early assistance to learn strategies for addressing them.
Set reasonable expectations. Residents may struggle with how they are perceived by their preceptors. The associated stress may accumulate throughout the year, resulting in lack of confidence, feelings of unease, and burnout. The wellness program at our institution gave residents and preceptors the opportunity to unite and address these topics upfront, set the standard for expectations and progression throughout the residency year, and alleviate the burden of troublesome worries and concerns.
Find meaningful downtime. Finding meaningful downtime activities between rotations and work shifts should be a goal for all residents. Meaningful downtime may differ from resident to resident, but that time should be spent doing an activity that appeals to and provides benefit to the resident. Though free time during residency is limited, the time available should be used wisely. Our Pharmacy Resident Wellness Program offers suggestions for activity sessions and actively encourages residents to acknowledge and act upon their need for meaningful downtime.
Be proud of and grateful for your own achievements. It is very easy for residents to focus on the negative aspects of life, but doing so creates a poor psychological environment. Our Pharmacy Resident Wellness Program provides us with tools to help us see ourselves positively and recognize the effort we display daily.
- Bridgeman PJ, Bridgeman MB, Barone J. Burnout syndrome among healthcare professionals. Am J Health Syst Pharm. 2018;75:147-152.
- Freudenberger HJ. Staff burn-out. J Soc Issues. 1974;50(1):159-165.
- Chatterjee R, Wroth C. WHO redefines burnout as a ‘syndrome’ linked to chronic stress at work. National Public Radio, Morning Edition, May 28, 2019. Accessed October 17, 2019. Available at https://www.npr.org/sections/health-shots/2019/05/28/727637944/who-redefines-burnout-as-a-syndrome-linked-to-chronic-stress-at-work.
- Le HM, Young SD. Evaluation of stress experienced by pharmacy residents. Am J Health Syst Pharm. 2017;74:599-604.
- Mayberry KM, Miller LN. Incidence of self-reported depression among pharmacy residents in Tennessee. Am J Pharm Educ. 2017;81(8):5960.
- Williams E, Martin SL, Fabrikant A, Wang A, Pojasek M. Rates of depressive symptoms among pharmacy residents. Am J Health Syst Pharm. 2018;75(5):292-297.
- Schernhammer ES, Colditz GA. Suicide rates among physicians: a quantitative and gender assessment (meta-analysis). Am J Psychiatry. 2004;161(12):2295-2302.
- Bowers P. Bridge jumper identified as Tosin Oyelowo. Charleston City Paper. December 19, 2011. Accessed October 17, 2019. Available at https://www.charlestoncitypaper.com/charleston/bridge-jumper-identified-as-tosin-oyelowo/Content?oid=3662179.
- Le HM, Young SD. Exploring the relationship between environmental stressors, pharmacy residents’ stress and medication errors. J Psychol Cognition. 2017;2(3):192-197.
- Flaxington BD. Developing time management skills: how to become more organized and find more time in a day. Psychology Today. July 27, 2015. Accessed October 17, 2019. Available at https://www.psychologytoday.com/us/blog/understand-other-people/201507/developing-time-management-skills.
- Vogel EA, Rose JP, Roberts L, Eckles K. Social comparison, social media, and self-esteem. Am Psych Assoc. 2014;3(4):206-222.
Deprescribing in Palliative Care: An Overview
Bradi L. Frei, PharmD MSc BCOP BCPS
Professor, Pharmacy Practice
Feik School of Pharmacy
University of the Incarnate Word
San Antonio, TX
Deprescribing is the practice of discontinuing potentially inappropriate prescription and nonprescription medications, including complementary and alternative medicine (CAM), in patients when the possible risks outweigh the benefits. Potentially inappropriate medications (PIMs) are largely referred to as medications lacking evidence-based indications, medications with treatment risks that may outweigh their benefits, medications associated with significant adverse reactions, and those that may potentially interact with other medications or diseases.1 This practice was initially developed for use in geriatric patients who had significant polypharmacy and limited life expectancy, but it has slowly been adopted in palliative care and oncology. Deprescribing has many benefits, including reducing medication costs, minimizing adverse drug effects, improving patients’ quality of life, improving adherence to beneficial medications, and decreasing the burden of polypharmacy in the last months of life.
Polypharmacy, frequently defined as taking five or more prescriptions concurrently for the treatment of one or more coexisting diseases, is common in older cancer patients.2 Polypharmacy in this setting can be appropriate if the additional medications are indicated and are benefiting the patient, but each added medication should be thoroughly assessed for benefits and risks. Trends in prescription drug use was evaluated by Kantor and colleagues with the National Health and Nutrition Examination Survey from 1992 to 2012.3 A significant increase in polypharmacy was seen over the years in all adult age and ethnic groups.3 During the 2011–2012 period, 39% of adults aged 65 years and older reported polypharmacy.
Cancer, often diagnosed in older patients, is difficult to treat, and the management of cancer symptoms and the adverse effects of treatment further complicate that treatment. The prevalence of polypharmacy at time of diagnosis in older acute myelogenous leukemia (AML) patients has been reported as 38%, with a median of four prescription medications prescribed.4 Several other clinical trials report an average of four to nine prescription medications per patient with 50%–69% of patients reporting use of CAM.4-6 Milic and colleagues reported that 37% of metastatic breast cancer patients were taking 10 or more tablets per day.7
The impact of polypharmacy in oncology patients has been evaluated in several studies. Woopen and colleagues analyzed prospective ovarian cancer trials to evaluate the influence of polypharmacy on grade 3/4 toxicity, prior discontinuation of chemotherapy, and survival.8 Increased medication use was associated with overall grade 3/4 toxicity (p < .001) and hematological (p < .001) and nonhematological (p < .001) toxicities. However, increased medication use was not associated with early discontinuation of chemotherapy (p = .196) or with overall survival (p = .068). In addition, Elliot and colleagues conducted a retrospective analysis of newly diagnosed AML patients (N = 150) and demonstrated that the total number of prescription medications at baseline was associated with increased 30-day mortality.4 The authors suggest that the increase in mortality could be caused by comorbidities and poorer health rather than resulting from an effect of polypharmacy. However, although an increased number of medications has been associated with chemotoxicity in some studies, overall results have been inconsistent, and many of the trials have not shown any adverse effects of PIMs. It is possible that some of the supportive care medications that could be classified as PIMs still have benefit to mitigate adverse effects from treatment in older patients.1
Several studies have described the common medications taken by patients near the end of life. Woopen and colleagues conducted a meta-analysis of three ovarian cancer trials (N = 1,213) and reported that the most frequent medications taken by the patients, besides those prescribed for symptomatic relief, were beta blockers (17.4%), diuretics (13.4%), and angiotensin-converting enzyme inhibitors (11%).8 Medications appropriate for deprescribing may seem evident in some cases, but others may have some positive attributes despite the negative ones. In addition, some prescribers may be reluctant to discontinue certain medications (e.g., proton pump inhibitors [PPIs] and statins) because of fear of adverse effects or other complications. PPIs are a mainstay in treating many acid-related disorders. Strong data support the short-term use of PPIs to control dyspepsia and gastroesophageal reflux disease (GERD). Because dyspepsia and other acid-related disorders can decrease a patient’s quality of life, the use of PPIs could be viewed as appropriate. However, long-term use of PPIs has been associated with hypergastrinemia, hypochlorhydria, idiosyncratic reactions, and pharmacokinetic interactions. Each of these can lead to health problems such as malabsorption of nutrients and tissue dysplasia.
Deprescribing of PPIs has been recommended for adults who are symptom-free after completion of a minimum 4-week PPI treatment for GERD.9 Kutner and colleagues conducted a randomized unblinded clinical trial that included 381 patients with limited life expectancy to evaluate the effects of statin deprescribing.10 Forty-eight percent of the patients had cancer. The primary outcome of death within 60 days was not different between the two groups (p = .36). Very few cardiovascular events occurred during the trial, with no difference between groups. Quality of life was statistically better in the group that discontinued statin use. Deprescribing was associated with cost savings of $3.37 per day and $716 per patient.
The geriatric literature describes several models for deprescribing, and a few models appear in oncology and palliative care literature. Scott and colleagues described a five-step process for eprescribing (Table 1 - see PDF).11 The first step in deprescribing is to perform medication reconciliation, including over-the-counter medications and medications used in CAM. The patient should be interviewed to determine the indication for the use of each medication; contacting the patient’s other providers to help determine the indication may also be necessary. After a determination has been made about which medications are to be discontinued, a decision can be made about which medications to stop first. When prioritizing drugs for discontinuation, the provider should choose to stop medications that have the greatest risk of harm and the least benefit, followed by those easiest to discontinue and then those that the patient is most willing to discontinue. Medications should be discontinued one at a time. The provider and patient should develop a written plan for discontinuation, including tapering instructions and a plan for follow-up and monitoring for any adverse effects of discontinuation. The provider should fully document the reasons for, and outcome of, discontinuation. Shared decision making is important in this process because deprescribing can have a psychological impact on both patients and caregivers. Deprescribing medication could be interpreted as having “given up on the patient” or believing that “the patient will soon die.” Other patients and caregivers may embrace having fewer medications and decreased medication costs.
(Table 2 - see PDF) lists common medication classes that are recommended to be tapered when they are being discontinued. A general rule of thumb when tapering is to decrease the dose by 50% for a prespecified amount of time and then decrease by 50% again or permanently discontinue the medication if a subsequent decrease is not feasible with the available dosage options. Tapering may take a week or up to several months depending on the medication and patient response. However, only one medication should be tapered or discontinued at a time.11
Tools for Deprescribing Medications
Several tools can help determine which medications should be discontinued; a list of available resources is given in (Table 3 - see PDF). The Beers Criteria, an explicit list of PIMs that are usually best avoided in older adults, is published by the American Geriatrics Society on a 3-year update cycle, with the most recent update published in 2019.12 In addition, the Medication Appropriateness Index (MAI) was developed in 1992 to identify PIMs by asking 10 questions that incorporate a 1–3 rating option depending on the appropriateness. The higher the score, the more likely it is that the medication is inappropriate for the patient. MAI is one of the few tools that also considers drug-drug interactions.13 The National Comprehensive Cancer Network (NCCN) Guidelines for Older Adult Oncology provides a list of medications that are commonly used for supportive care and that are a concern in older cancer patients. The guideline provides recommendations and alternative options for commonly prescribed supportive care medications.14 The Screening Tool of Older Persons’ Prescriptions (STOPP) criteria note the medications that increase the risk of falls and those with a high chance of adverse events (drug-drug and drug-disease interactions are included).15 These are explicit criteria for determining optimal prescribing and can be applied to most patients. The Drug Burden Index was developed to measure the cumulative exposure to medications with anticholinergic and sedative effects in older adults and its impact on physical and cognitive function.16
The MedStopper online tool (MedStopper.com) incorporates data from the Beers Criteria, STOPP, and the Drug Burden Index.17 The tool allows multiple medications to be entered along with the associated indication. Of note, not all common indications are currently listed. For example, when warfarin, an anticoagulant, is entered, no deep vein thrombosis treatment or prevention indication is given. Also, no nausea or vomiting indication option is provided for prochlorperazine, a common antiemetic. However, an “unknown” indication option is available in these situations. Smiley and frowny faces indicate the extent to which the medicine may improve symptoms, may reduce risk for future illness, or may cause harm. The recommendations can be modified for frail or fit patients. The tool is very user-friendly and provides analysis of the medications, including suggestions for deprescribing and tapering. The analysis can be printed to aid the provider when discussing deprescribing with patient and caregivers. The smiley and frowny faces and colors can be easily understood by most patients, and reports are available in both English and French.
Additional information and decision aid tools on deprescribing can be found at www.deprescribing.org.18 The website was developed and is supported by a pharmacist and physician who work with older patients and are concerned about the risks associated with medications at the Bruyère Research Institute (Ottawa) and Université de Montréal. The available information includes webinars and other educational tools about deprescribing for healthcare professionals.
Barriers to Deprescribing
Although deprescribing has many benefits for patients, some barriers for the process exist, including a reluctance to cease medications prescribed by specialists, the perception of inability to change patients’ attitudes, and the belief that a strong indication for a medication existed. Djatche and colleagues surveyed 160 Italian physicians concerning their attitudes about deprescribing in elderly patients who were not primarily cancer patients.19 The majority of physicians surveyed were primary care physicians, and only 5% were hematology specialists. Seventy-eight percent of the physicians were comfortable deprescribing preventive medications in elderly patients, and 40% of physicians reported hesitance in discontinuing medications prescribed by other prescribers. One in four physicians reported lack of time and difficulty engaging the patient or caregiver as barriers to deprescribing.
In 2013, Reeve and colleagues published a study evaluating attitudes about deprescribing for patients with multiple comorbidities.20 Of the 100 Australian participants, 92% reported being willing to stop one or more medications if possible. In a separate study, Reeve and colleagues evaluated 1,981 United States Medicare beneficiaries using the Patients’ Attitudes Towards Deprescribing Questionnaire.21 Ninety-two percent of participants reported being willing to stop taking one or more of their medications if their physician agreed. Overall, more than two-thirds of participants wanted to reduce the number of medications they were taking.
Overall, research does not support the hypothesis that barriers toward deprescribing are prevalent among patients. Physicians are open to deprescribing, but they are reluctant to deprescribe medications initiated by another prescriber. The research pertaining to deprescribing statin medications and PPIs initiated by a specialist or during hospitalization provides helpful guidance for some cases,9,10 but further research and education may be needed to increase comfort with deprescribing, especially in cancer patients, in other situations.Deprescribing medications is an important part of the care of all patients, including cancer patients, near the end of life. Medications once taken to ensure long-term health are often no longer a beneficial choice and may have more health risks than benefits. Oncology and palliative care pharmacists are in an ideal position to help in the deprescribing process because they are aware of the patient’s prognosis and medications. Deprescribing can decrease the burden of polypharmacy, decrease medication costs, and reduce possible adverse drug reactions and interactions. For these reasons, deprescribing is an appropriate step for patients near the end of life.
- Sharma M, Loh KP, Nightingale G, Mohile SG, Homes HM. Polypharmacy and potentially inappropriate medication use in geriatric oncology. J Geriatr Oncol. 2016;7:346-353.
- Lees J, Chan A. Polypharmacy in elderly patients with cancer: clinical implications and management. Lancet Oncol. 2011;12:1249-1257.
- Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL. Trends in prescription drug use among adults in the United States from 1999-2012. JAMA. 2015;314:1818-1831.
- Elliot K, Tooze JA, Geller R, et al. The prognostic importance of polypharmacy in older adults treated for acute myelogenous leukemia (AML). Leuk Res. 2014;38:1184-1190.
- Cashman J, Wright J, Ring A. The treatment of co-morbidities in older patients with metastatic cancer. Support Care Cancer. 2010;18:651-655.
- Sokol KC, Knudsen JF, Li MM. Polypharmacy in older oncology patients and the need for an interdisciplinary approach to side-effect management. J Clin Pharm Ther. 2007;32:169-175.
- Milic M, Foster A, Rihawi K, Anthoney A, Twelves C. ‘Tablet burden’ in patients with metastatic breast cancer. Eur J Cancer. 2016;55:1-6.
- Woopen H, Richter R, Ismaeel F, et al. The influence of polypharmacy on grade III/IV toxicity, prior discontinuation of chemotherapy and overall survival in ovarian cancer. Gynecol Oncol. 2016;140:554-558.
- Helgadottir H, Bjornsson ES. Problems associated with deprescribing of proton pump inhibitors. Int J Mol Sci. 2019;20:E5469.
- Kutner JS, Blatchford PJ, Taylor DH Jr, et al. Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial. JAMA Intern Med. 2015;175:691-700.
- Scott IA, Hilmer SN, Reeve E, et al. Reducing inappropriate polypharmacy: the process of deprescribing. JAMA Intern Med. 2015;175:827-834.
- 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67:674-694.
- Hanlon JT, Schmader KE. The medication appropriateness index at 20: where it started, where it has been, and where it may be going. Drugs Aging. 2013;30:893-900.
- National Comprehensive Cancer Network. Older Adult Oncology (Version 1.2019). http://www.nccn.org/professionals/physician_gls/pdf/senior.pdf. Accessed: December 29, 2019.
- O’Mahony D, O’Sullivan D, Byrne S, O’Connor MN, Ryan C, Gallagher P. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2. Age Ageing. 2015;44:213-218.
- Hilmer SN. Calculating and using the drug burden index score in research and practice. Expert Rev Clin Pharmacol. 2018;11:1053-1055.
- MedStopper. MedStopper deprescribing resource. Available at http://medstopper.com/. Accessed December 29, 2019.
- Bruyere. Optimizing medication use. Available at http://deprescribing.org/. Accessed: December 29, 2019.
- Djatche L, Lee S, Singer D, Hegarty SE, Lombardi M, Maio V. How confident are physicians in deprescribing for the elderly and what barriers prevent deprescribing? J Clin Pharm Ther. 2018;43:550-555.
- Reeve E, Wiese MD, Hendrix I, Roberts MS, Shakib S. People’s attitudes, beliefs, and experiences regarding polypharmacy and willingness to deprescribe. J Am Geriatr Soc. 2013;61:1508-1514.
- Reeve E, Wolff JL, Skehan M, Bayliss EA, Hilmer SN, Boyd CM. Assessment of attitudes toward deprescribing in older Medicare beneficiaries in the United States. JAMA Intern Med. 2018;178:1673-1680.
Financial Toxicity in Cancer Care
Laura Cannon, PharmD MPH
Clinical Assistant Professor and Oncology Pharmacist
The University of Texas at Austin College of Pharmacy
and Dell Medical School Livestrong Cancer Institutes
Chelsea Gustafson, PharmD BCOP
Oncology Pharmacy Specialist
Community Health Network: Community Regional
Caroline Quinn, PharmD BCOP
Clinical Pharmacy Specialist
The University of Texas MD Anderson Cancer Center >
If you spend a day in an oncology clinic, in only a few minutes you will hear discussion about the prevention or treatment of common toxicities. Myelosuppression, neuropathy, diarrhea, and nausea and vomiting are routinely discussed toxicities in the management of cancer care. Financial toxicity, however, may not be the first toxicity that comes to mind, or it may not even be considered at all.
Financial toxicity in cancer care can be viewed through many lenses. In our work on this article, we took the opportunity to interview four individuals who have distinct roles in cancer care: an oncology nurse practitioner, an oncology pharmacist, an oncology clinical social worker, and a pharmacy technician who works as an outpatient medication assistance coordinator. We asked them several questions about financial toxicity. It is our hope that the answers below (which contain our own thoughts and those of the four professionals) will highlight areas for improvement in clinical practice.
How do you define financial toxicity of cancer care?
As pharmacists, we often think of financial toxicity as the cost of cancer treatments. We know that these costs continue to increase, especially for newer treatment options like immunotherapy and oral chemotherapies.1 Medication assistance coordinator Samantha Shaver states that “patients who are newly diagnosed not only worry about life-changing news but also have to worry about the affordability of treatment while maintaining the normal costs of living.” When considering the cost of medication therapy alone, “clinic staff members should be cognizant of how their patients are tolerating the treatment financially,” according to pharmacist Ashish Suthar. “Patients may be just as likely to dose-reduce or stop treatment on their own because of cost, just as we would for a lab abnormality.”
But financial toxicity may extend beyond the cost of medications. Oncology nurse practitioner Anne Courtney defines financial toxicity as “any cost of cancer treatment that alters the way people may make treatment decisions or that impacts their ability to live their baseline life.” This extends beyond medication therapy, because cancer treatment can include surgery, radiation, frequent office visits, and lab tests. The cost of medication therapy alone can be high, but it does not exist in a vacuum and should be viewed in combination with all potential causes of financial toxicity for cancer patients and their loved ones. Oncology clinical social worker Angela Luna adds, “Financial toxicity is what happens when healthcare costs eat up so much of a family’s disposable income that they can’t afford daily necessities, much less save for the future.” Her perspective introduces financial toxicity as not just a concern for the present but something that may extend far beyond the time of the initial diagnosis and treatment.
In your opinion, what are the biggest financial issues for cancer patients right now?
Each of our four respondents (nurse practitioner, clinical social worker, pharmacist, and medication assistance coordinator) identified a different area as the biggest financial concern for cancer patients. They spoke about the cost of medication therapy and the frequency of treatments, the cost of copayments for diagnostic imaging, the cost of hospital and emergency department admissions, worries about being underinsured (having insurance but with either costly copayments for every aspect of care or else high deductibles), and the need for patients and healthcare providers to have better access to information on assistance programs. This list highlights the need for awareness of financial toxicity from all disciplines and perspectives, because the overall costs of cancer care can quickly accumulate.
Clinicians may be aware of costs related to their own areas of practice but fail to view the overall financial situation, which identifies an additional area of need. Luna points out that “financial toxicity is a tricky area because you really need an expert who knows the ins and outs of all the resources and strategies. The irony is that many institutions don’t prioritize that in their funding of positions. This situation means that dealing with these issues is left to people who are trying their best but may not be operating in their area of expertise.” Suthar adds, speaking specifically about medication-related costs, “Depending on the size of the practice, it could take one (or more) full-time staff members to help patients find and enroll in assistance programs.”
The other difficulty in navigating through concerns about financial toxicity is the fact that cancer care costs are not always known upfront, and our responses are often reactive rather than proactive. Healthcare organization and insurance disclosures about upfront costs for procedures, imaging, medications, and office visits could shift this paradigm. In addition, Luna suggests that more detailed education on the selection of insurance plans could offset the problem of patients’ being underinsured.
What strategies do you employ to help patients overcome the financial toxicity of cancer care?
Current strategies to combat financial toxicity include the use of drug manufacturers’ copay cards, patient assistance programs, and disease-based grant funding for medication copay assistance. However, Shaver notes that some of the biggest difficulties she deals with are finding grants and funding related to rare diagnoses and off-label medication uses, in addition to accessing assistance with deductible payments for commercially insured patients. Suthar suggests keeping a list of resources and documents (phone numbers, points of contact, and eligibility and documentation requirements for various assistance programs) and connecting with field reimbursement representatives in drug companies who can help break down barriers to getting patients access to medications. He also recommends using online portals for real-time feedback. Courtney’s strategy is proactive: she ensures that she “provides the best patient education to decrease toxicities and risks that may lead to the patient missing work or being admitted to the hospital.” She highlighted the need to tackle financial toxicity from all angles. Luna points out that sometimes the only course of action is to help patients shift costs based on available resources. For example, you may find resources to assist with transportation so that patients can then apply the money saved toward another cost.
We have many opportunities to improve how we manage the financial toxicity of cancer care. Institutions must make this improvement a priority because patients’ inability to receive all aspects of care because of concerns about cost can have a negative impact on overall outcomes and survival. With rising healthcare and medication costs, this problem will only become more serious. Just as we assess for treatment-related toxicity during each visit, we should also assess a patient’s risk for financial toxicity, particularly at high-risk points such as treatment initiations, dose changes, or changes in a patient’s insurance. Although the perspectives shared here do not address all the problems, they show the variety of contributing factors and management strategies and highlight the importance of teamwork and interprofessional collaboration to help reduce the financial burden for cancer patients and their loved ones.
We thank oncology nurse practitioner Anne Courtney, DNP ACNP, pharmacy manager Ashish Suthar, PharmD MJ, oncology clinical social worker Angela Luna, LCSW, and medication assistance coordinator Samantha Shaver, CPhT, for the gift of their time and for their thoughtful contributions to this article.
Request for Contributions of Best Practices
- Prasad V, De Jesus K, Mailankody S. The high price of anticancer drugs: origins, implications, barriers, solutions. Nat Rev Clin Oncol. 2017;14:381-390.
Highlights of 2019 HOPA Practice Management
Julianne O. Darling, PharmD BCOP
Outpatient Oncology Clinical Specialist
Indiana University Simon Cancer Center
The 2019 Hematology/Oncology Pharmacy Association Practice Management program1 was held in Charlotte, NC, on Friday, September 13, and Saturday, September 14. This meeting offered both live and virtual participation, and attendees included 250 hematology and oncology pharmacists and administrators from across the country.
Three preconference sessions were offered on September 13: “Investigational Drug Services” (covering safety, standards, and regulatory issues), “The Growing Role of Specialty Pharmacy as an Extension of the Cancer Care Team,” and “Best Practices for Cancer Care at Integrated Delivery Networks.” In addition, a Quality Improvement (QI) Workshop was held on September 12. This workshop was organized by the HOPA Quality Oversight Committee as an introduction to the American Society of Clinical Oncology (ASCO) Quality Training Program (QTP). Thirty-one HOPA members attended this workshop to learn about the components of QI in health care from ASCO QTP leaders Michael Keng, MD; Vedner Guerrier, MBA LSSBB; and Amy Morris, PharmD. (See HOPA News, Vol. 16, no. 4, for additional coverage of this workshop.)
The general sessions kicked off at noon on Friday with a presentation on the practical implementation of biosimilars. This session included comments from three pharmacists (two working with Kaiser Permanente and one working with BlueCross BlueShield of North Carolina) about considerations for payers and providers related to biosimilar use. Next, Russell Greenfield, MD, gave the presentation “Integrative Oncology: Separating Wheat from Chaff.” Dr. Greenfield discussed the expanding role of the pharmacist and included a number of patient scenarios to highlight the need for healthcare providers to communicate with patients regarding integrative or alternative medications. One study noted that 38% of the American population is interested in complementary or alternative medicine, and interest is even higher in the cancer population (up to 68%).2 Above all else, Dr. Greenfield emphasized the need for pharmacists to take the lead in supporting the well-being of each patient through safely managing patients’ use of vitamins, supplements, and herbs in addition to their traditional cancer treatment.
Along with the continuing education programming offered at the meeting, a number of presentations and networking events allowed attendees the opportunity to get to know one another. On Friday evening an update on HOPA’s Pilot Mentorship Program was led by Becky Fahrenbruch, PharmD BCOP. This program was developed by the Leadership Development Subcommittee to gauge interest in a mentorship program for HOPA and determine the best steps for implementing such a program. This year, five pairs of mentees and mentors met in monthly calls to discuss various leadership topics. In conjunction with the monthly calls, the group participated in a meet-and-greet event at HOPA’s 2019 Annual Conference in Fort Worth, TX. To conclude the pilot program, the group met for breakfast during HOPA’s 2019 Practice Management program to discuss the book Conscious: The Power of Awareness in Business and Life, by Bob Rosen and Emma-Kate Swann. The book-club breakfast was a great occasion for the participants to get to know one another and learn from the mentors’ involvement in HOPA over the years.
Friday night concluded with a presentation by Heidi Finnes, PharmD BCOP, titled “You Can Move Mountains.” Dr. Finnes discussed her nontraditional path to becoming a pharmacy leader and the ways that her melanoma diagnosis helped her gain perspective both personally and professionally. This session was informative and inspirational: Dr. Finnes gracefully discussed her experience as both a patient and a provider and helped the audience understand how these experiences shaped her leadership skills and management style. Her humble but impactful presentation left the audience feeling motivated and eager for day 2.
Saturday opened with a general session by Jason Bonner, PhD, on healthcare provider burnout and key strategies for developing resilience. Alarmingly, pharmacy ranks among the top professions with the highest rates of suicide. Dr. Bonner reviewed an article by Durham and colleagues revealing that pharmacists who had less than 15 years of experience were at higher risk of burnout.3 As a new practitioner, I was struck by this statistic, which really shifted my perspective on burnout. In his discussion of ways to develop resilience, Dr. Bonner highlighted the need for social support, optimism and confidence, effective communication, and the ability to manage powerful emotions and impulses.
Saturday’s later sessions included “Value-Based Care and the Role of Medication Optimization,” “Regulatory Updates,” “Strategies to Overcome Site-of-Care Restrictions,” and “Generational Differences.” Steven Gilmore, PharmD BCOP, Rowena Schwartz, PharmD BCOP FHOPA, and Damary Torres, PharmD, led the panel discussion of generational differences. The panelists described evidence-based differences between generations (Millennials, Generation X, Baby Boomers, and Generation Z) and ways to optimize collaboration between members of different generations. They reviewed positive and negative qualities attributed to each generation and discussed with the audience how to use each generation’s strengths to enhance teamwork.
The conference concluded Saturday afternoon with the keynote address “CPR for the Oncologist’s Soul” by Steven Eisenberg, DO. Dr. Eisenberg opened by expressing his appreciation for oncology pharmacists and the teamwork that is such an integral part of oncology care. He highlighted the ways that stress and anxiety have an impact on healthcare providers. In his heartfelt presentation, Dr. Eisenberg demonstrated how one of his patients changed his perspective on burnout through “the Flavie Effect.” Flavie, one of his patients, taught him that illness starts with ‘I,’ and wellness starts with ‘we.’ ” Throughout his address, Dr. Eisenberg emphasized the need for everyone to have Connection, be Present, and develop Resilience—CPR.
HOPA’s 2020 Annual Conference will be held March 11–14, 2020, in Tampa, FL, and the 2020 Practice Management program will be held September 11–12, 2020, in Houston, TX.
- Hematology/Oncology Pharmacy Association. 2019 Practice Management(courseschedule and session descriptions).
- Johnson SB, Park HS, Gross CP, Yu JB. Use of alternative medicine for cancer and its impact on survival. J Natl Cancer Inst. 2018 January 1;110(1):121-124. Available at https://doi.org/10.1093/jnci/djx145
- Durham ME, Bush PW, Ball AM. Evidence of burnout in health-system pharmacists. Am J Health Syst Pharm. 2018 December 1;75(23 Supplement 4):S93-S100. Available at https://doi.org/10.2146/ajhp170818. Epub 2018 October 17.
Peripheral Neuropathy in Non-Hodgkin Lymphoma Patients Receiving Vincristine With and Without Aprepitant/Fosaprepitant
John B. Bossaer, PharmD BCOP BCPS
Bill Gatton College of Pharmacy
East Tennessee State University
Johnson City, TN
Vincristine is a widely used agent in hematologic malignancies. Its efficacy and lack of myelosuppression make it an ideal antimicrotubule agent to include in combination chemotherapy regimens. Despite the widespread use of vincristine, dose-limiting peripheral neuropathy can occur. Risk factors for peripheral neuropathy include hepatic dysfunction (e.g., elevated total bilirubin) and concomitant use of CYP3A4 inhibitors (e.g., azole antifungals).
The antiemetic agent aprepitant and its IV formulation prodrug, fosaprepitant, are moderate CYP3A4 inhibitors. Aprepitant/fosaprepitant’s CYP3A4 inhibition is illustrated by the dosing of dexamethasone, a CYP3A4 substrate, with and without concomitant aprepitant (12 mg vs. 20 mg, respectively).1 It has been widely assumed that no significant drug-drug interaction between vincristine and aprepitant/fosaprepitant occurs. This assumption likely stems from a small pharmacokinetic study (N = 12) demonstrating similar plasma concentrations of vinorelbine when it is given with and without aprepitant.2 Vinorelbine, also a vinca alkaloid, has minor differences in metabolism and elimination compared to vincristine, but both are primarily metabolized via CYP3A4.
However, Okada and colleagues identified aprepitant use as a risk factor for early-onset (after the first cycle) vincristine-induced peripheral neuropathy in Japanese patients receiving cyclophosphamide doxorubicin vincristine prednisone (CHOP)–like chemotherapy regimens.3 Given the biological plausibility of an aprepitant/fosaprepitant-vincristine interaction via CYP3A4 inhibition and these recent clinical data from Okada and colleagues, we decided to investigate the possibility of such an interaction in our patient population. Anecdotally, the ratio of local oncologists who routinely prescribe neurokinin-1 (NK-1) antagonists (aprepitant and fosaprepitant are the only NK-1 agents on formulary) with CHOP-like regimens is approximately 50:50. Therefore, we believed that a retrospective cohort study of CHOP-like chemotherapy patients who did or did not receive aprepitant/fosaprepitant would be feasible.
We retrospectively reviewed electronic medical records from July 1, 2010, to June 30, 2018, of all adults who received standard-dose vincristine-based chemotherapy regimens for non-Hodgkin lymphoma (NHL).4 The primary objective of our study was the incidence of early-onset peripheral neuropathy, with a secondary endpoint of cumulative rate of peripheral neuropathy. The incidence of peripheral neuropathy was determined by reviewing medical records for documented neuropathy symptoms or initiation of treatment for peripheral neuropathy (e.g., gabapentin). We determined that 186 patients would be needed to have 80% power to detect a 20% difference in early-onset peripheral neuropathy between the aprepitant/fosaprepitant group and the group that did not receive an NK-1 antagonist. Fisher’s exact test was used to analyze primary and secondary endpoints with a one-side alpha of 0.05.
Ultimately, 115 patients were eligible for evaluation. The most common reason for exclusion was a cancer other than NHL (n = 23), multiple doses of vincristine/cycle (n = 12), lost to follow-up (n = 9), death (n = 9), and prior vincristine use (n = 8). More patients received aprepitant/fosaprepitant (n = 71) than did not (n = 44). However, baseline demographics were similar between the two groups regarding concomitant use of other 3A4 inhibitors such as fluconazole, vincristine dose, and age. There were fewer patients with diabetes in the aprepitant/fosaprepitant group (21.2% vs. 38.6%; p = .04). CHOP, rituximab-CHOP (R-CHOP), and rituximab cyclophosphamide vincristine prednisone (R-CVP) were the most common chemotherapy regimens in both groups (80.2% and 72.7%, respectively). There was no difference in the rate of early-onset peripheral neuropathy between groups (26.7% vs. 22.7%; p = .627). However, more overall peripheral neuropathy was seen in the aprepitant/fosaprepitant group (56% vs. 36%; p = .036). All cases of peripheral neuropathy were mild (grade 1).
The results suggest that CYP3A4-inhibiting NK-1 antagonists (aprepitant, fosaprepitant, netupitant) increase the risk of vincristine-induced peripheral neuropathy. However, one must consider the quality of evidence and balance that with the efficacy of NK-1 antagonists in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV). Certainly, our study suffers from several notable limitations. First and foremost, retrospective studies are subject to confounding variables, and any such results should be interpreted as hypothesis-generating rather than practice-changing. In addition, we included patients who were receiving treatment with common 3A4 inhibitors (such as fluconazole and diltiazem) to better represent real-world practice. Although the use of such drugs was well balanced between the groups, this inclusion may still confound results. Finally, our study was small and underpowered for our primary endpoint.
Given the quality of the evidence and the fact that all cases of peripheral neuropathy were mild, clinicians should feel comfortable using aprepitant or fosaprepitant with vincristine-containing regimens in patients at high risk of CINV. Given the frequency that CHOP-like regimens are administered with and without NK-1 antagonists at cancer centers around the country, similar studies should be conducted to better delineate the risk of vincristine-induced peripheral neuropathy with CYP3A4-inhibiting NK-1 antagonists. If you are reading this, please consider conducting such a study! Future considerations should include the possibility that longer 3A4 inhibition with aprepitant (given orally for 3 days) or netupitant (with a longer half-life) is a greater risk than fosaprepitant (given IV for 1 day), as well as the possible risk with vincristine-intensive regimens (e.g., EPOCH). One might also consider making a comparison of rolapitant use versus aprepitant/fosaprepitant, because rolapitant is not a 3A4 inhibitor. Of course, a prospective study with similar cohorts would be ideal and would provide clinicians with higher-quality evidence.
- McCrea JB, Majumdar AK, Goldberg MR, et al. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther. 2003;74:17-24.
- Loos WJ, de Wit R, Freedman SJ, et al. Aprepitant when added to a standard antiemetic regimen consisting of ondansetron and dexamethasone does not affect vinorelbine pharmacokinetics in cancer patients. Cancer Chemother Pharmacol. 2007;59:407-412.
- Okada N, Hanafusa T, Sakurada T, et al. Risk factors for early-onset peripheral neuropathy caused by vincristine in patients with a first administration of R-CHOP or R-CHOP-like chemotherapy. J Clin Med Res. 2014;6:252-260.
- Edwards JK, Bossaer JB, Lewis PO, Sant A. Peripheral neuropathy in non-Hodgkin’s lymphoma patients receiving vincristine with and without aprepitant/fosaprepitant. J Oncol Pharm Pract. 2019. Published online ahead of publication on August 25, 2019.
Larotrectinib and Entrectinib: A Golden Ticket for Adult and Pediatric Patients with NTRK Gene Fusion?
Hansen Ho, PharmD BCOP
Associate Clinical Professor
UCSF Helen Diller Comprehensive Cancer Center
UCSF School of Pharmacy, Department of Clinical Pharmacy
San Francisco, CA
A new class of anticancer agents has joined pembrolizumab as tissue-agnostic treatment options for solid tumor cancers. Pembrolizumab, an immune checkpoint inhibitor that targets the programmed cell death-1 (PD-1) pathway, was the first U.S. Food and Drug Administration (FDA)–approved tissue-agnostic agent targeting tumors with high microsatellite instability or DNA mismatch repair deficiency (dMMR) as a surrogate marker for high-somatic mutations.1,2 Pembrolizumab’s tissue-agnostic approval added to the solid-tumor armamentarium based only on a tumor marker. Larotrectinib and entrectinib, which are tropomyosin receptor kinase (TRK) small-molecule inhibitors, are the second class of tissue-agnostic anticancer agents approved by the FDA, specifically for adult and pediatric patients with NTRK gene fusion.3,4 The NTRK genes NTRK1, NTRK2, and NTRK3 encode TRK proteins TRKA, TRKB, and TRKC, respectively. TRK expression is primarily limited to embryogenesis and regulation of the central nervous system (CNS).5 Somatic gene fusions involving the NTRK family of genes and subsequently downstream TRK fusion protein overexpression are implicated in driving proliferation in multiple solid tumors.
In common cancers, NTRK gene fusions are extremely rare, occurring in 0.1%–2% of patients as determined by highly sensitive next-generation sequencing (NGS).6 However, there is widespread variability in this incidence and bias, depending on the type of test used for NTRK gene fusions, with colorectal, appendiceal, and lung cancers and cancers such as sarcomas, melanomas, cholangiocarcinomas, and gliomas reportedly having an incidence of <5%. In certain exceedingly rare tumors, such as pediatric infantile fibrosarcomas, adult salivary gland tumors, and secretory breast cancers, the incidence of NTRK gene fusion is much higher, greater than 75%.6 Other rare tumors, such as thyroid carcinomas, congenital mesoblastic nephromas, and spitzoid melanomas, have reported incidences of 5%–75%, illustrating testing bias and variability in clinical laboratory technique.6 Detecting a NTRK gene fusion signal can currently be challenging, but its identification can give patients a long-term benefit.
Larotrectinib was approved on the basis of three phase 1 studies, the LOXO-TRK-14001, SCOUT, and NAVIGATE trials, involving 55 adults and children with TRK fusion–positive tumors.7 Eligible patients had locally advanced or metastatic disease and had exhausted standard-of-care treatments. Of the 55 patients, 17 unique cancer diagnoses were identified, with the majority of patients (n = 30) having salivary gland carcinomas, soft tissue sarcomas, or pediatric fibrosarcomas. In addition, only one patient had evidence of CNS metastasis in the pooled data. At primary data cutoff, the overall response rate by independent radiologic review was 75% (95% confidence interval [CI], 61–85).6 A total of 13% of patients had a complete response (CR), 62% had a partial response (PR), 13% had stable disease (SD), and 9% had progressive disease (PD).7 The median duration of response (DOR) and progression-free survival (PFS) had not been reached after the median follow-up duration of 8.3 and 9.9 months, respectively.7 At 1 year, 71% of responses were ongoing, and 55% of responding patients remained progression free. At data cutoff, 86% of the patients with a response were continuing to receive treatment or had undergone curative surgery.7 Acquired resistance was detected in 19 patients receiving larotrectinib from kinase domain mutations, which may have important implications in the development of second-generation NTRK inhibitors.7
Updated data presented at the European Society for Medical Oncology Congress 2019 that now includes 153 patients continued to demonstrate a high overall response rate (ORR) of 79% (95% CI, 72–85), with 16% with a CR and 63% with a PR.8 Median DOR was 35.2 months (95% CI, 22.8 to not evaluable [NE]), median PFS was 28.3 months (95% CI, 22.1 to NE), and median overall survival (OS) was 44.4 months (95% CI, 36.5 to NE).8 Additional subgroup analysis showed a response rate of 75% in solid tumors with brain metastasis demonstrating CNS activity.9
An examination of adverse events from the LOXO-TRK-14001, SCOUT, and NAVIGATE trials showed that, overall, larotrectinib was well tolerated. The most common adverse reactions (all grades ≥ 20%) include fatigue, nausea, dizziness, vomiting, anemia, increased aspartate aminotransferase (AST)/alanine aminotransferase (ALT), cough, constipation, and diarrhea.10 Dose modifications were required in 37% of patients because of increased AST/ALT and dizziness.10
Entrectinib was approved on the basis of early-phase pooled analysis of three studies, the STARTRK-1, STARTRK-2, and ALKA-372-001 trials, composed of 54 adult patients with NTRK fusion–positive metastatic or advanced tumors with or without brain metastasis. Results demonstrated a high ORR of 57.4% (95% CI, 43.2–70.8) with 7.4% of patients achieving a CR.4 Median DOR was 10.4 months (95% CI, 7.1 to not reached [NR]), PFS was 11.2 months (95% CI, 8–14.9), and median OS was 20.9 months (95% CI, 14.9 to NR).11
In adult patients with brain metastasis (n = 12) across the three studies, ORR was consistent with patients without brain metastasis at 50%, with median PFS of 7.7 months (95% CI, 4.7 to NR).11 In addition, intracranial ORR was 54.5% in patients with baseline CNS disease, demonstrating entrectinib’s activity across the blood-brain barrier.11
Approval of entrectinib for pediatric patients was based on early results from the phase 1/1b study STARTRK-NG that enrolled 29 patients with primary CNS tumors, neuroblastomas, and other solid tumors with NTRK fusions, ROS1 fusions, or ALK fusions. Of six patients with CNS tumors, one patient achieved a CR, three patients achieved a PR, and two patient responses were yet to be confirmed.12 Of eight patients with extracranial solid tumors, six patients responded, including two ALK-fusion patients who obtained a CR and PR, three NTRK-fusion patients who obtained a PR, and one ROS1-fusion patient who obtained a PR. Median time to response was 57 days (30–58 days).12 The median duration of therapy was 85 days (6–592 days) for all patients, 56 days (6–338 days) for nonresponders, and 281 days (56–592 days) for responders.12
Adverse events with entrectinib were seen in NTRK fusion, ROS1 mutation–positive, and ALK mutation–positive patients. Examining the safety profile from STARTRK-1, STARTRK-2, STARTRK-NG, and ALKA-372-001 trials showed that entrectinib was well tolerated.9 The most common toxicities (all grades ≥ 20%) include fatigue, edema, pyrexia, constipation, diarrhea, nausea, vomiting, dizziness, dysgeusia, dysesthesia, and myalgias. Dose reductions were required in 29% of patients because of dizziness, fatigue, anemia, increased creatinine, and weight gain.13
NTRK Gene Fusion Testing
The major hurdle in treating patients with larotrectinib or entrectinib is appropriately detecting patients with NTRK gene fusions. Approaches that may be used to directly or indirectly detect the presence of gene fusion include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), reverse transcriptase polymerase chain reaction (RT-PCR), and RNA or DNA NGS.14 IHC, FISH, and RT-PCR are low cost and readily available but are associated with a higher proportion of false-positive and false-negative results. IHC enables detection of TRK overexpression as a surrogate marker for NTRK fusion proteins, leading to possible detection of nonpathogenic fusions.14 FISH and RT-PCR require a known target sequence to detect NTRK 5' fusions, which may lead to missing novel NTRK fusions and subsequently result in false negatives.14 NGS provides a precise method of detecting known and novel NTRK gene fusions, but its availability varies by region.14 Testing algorithms are still in development; a staged strategy has been proposed. Tumors with a high frequency of NTRK gene fusions, such as pediatric infantile fibrosarcomas and secretory breast cancers, can be screened with IHC or FISH and reflex to NGS to account for false-negative results.14,15 The treatment of tumors with a low frequency of NTRK gene fusion, such as colon cancer or lung cancer, should proceed directly to NGS.14
Positive early-phase studies have demonstrated high response rates and durable responses with larotrectinib and entrectinib in adult and pediatric patients with NTRK gene fusions. Similar to the results of microsatellite instability–high or dMMR testing, a positive signal can provide an extra line of therapy for patients with solid tumors. In the future, long-term follow-up and further studies are needed to determine differences in safety and efficacy between larotrectinib and entrectinib. Adult and pediatric pharmacists in all solid-tumor subspecialties should assess for the opportunity to advocate for NTRK gene fusion testing to potentially find a golden ticket for patients on their last line of treatment.
- U.S. Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm. Accessed November, 17, 2019.
- Le DT, Uram JN, Wang H, et al. PD-1 blockage in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-2520.
- U.S. Food and Drug Administration. FDA approves larotrectinib for solid tumors with NTRK gene fusions. Available at https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions-0. Accessed November 17, 2019.
- U.S. Food and Drug Administration. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-entrectinib-ntrk-solid-tumors-and-ros-1-nsclc. Accessed November 17, 2019.
- Chao MV. Neurotrophins and their receptors: a convergence point for many signaling pathways. Nat Rev Neurosci. 2003;4:299-309.
- Hsiao SJ, Zehir A, Sireci AN, Aisner DL. Detection of tumor NTRK gene fusions to identify patients who may benefit from tyrosine kinase (TRK) inhibitor therapy. J Mol Diagn. 2019;21:553-571.
- Drilon A, Laetsch TW, Kummar SG, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378:731-739.
- Hyman DM, van Tilburg CM, Albert CM, et al. Durability of response with larotrectinib in adults and paediatric patients with TRK fusion cancer. Presented at ESMO Congress 2019; September 27–October 1, 2019; Barcelona, Spain. Poster 445PD.
- Drilon AE, DuBois SG, Farago AF, et al. Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors. J Clin Oncol. 37;15 suppl. 2006.
- Vitrakvi (larotrectinib) [package insert]. Whippany, NJ. Bayer HealthCare Pharmaceuticals, Inc.; July 2019.
- Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive (NTRK-fp) tumors: pooled analysis of STARTRK-2, STARTRK-1, ALKA -372-001. Presented at ESMO Congress, October 21, 2018, Munich, Germany. Poster LBA17.
- Robinson GW, Gajjar AJ, Gauvain KM, et al. Phase 1/1b trial to assess the activity of entrectinib in children and adolescents with recurrent or refractory solid tumors including central nervous system (CNS) tumors. J Clin Oncol. 2019;37;15-suppl:10009.
- Rozlytrek (entrectinib) [package insert]. South San Francisco, CA: Genentech USA, Inc.; 2019
- Penault-Llorca F, Rudzinski ER, Sepulveda AR. Testing algorithm for identification of patients with TRK fusion cancer. J Clin Pathol. 2019;72:460-467.
- Albert CM, Davis JL, Federman N, Casanova M, Laetsch TW. TRK fusion cancers in children: a clinical review and recommendations for screening. J Clin Oncol. 2019;37:513-524.