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

View PDF of HOPA News, Vol. 17, no. 3

Board Update: Accelerating to the Next Chapter

David DeRemer, PharmD BCOP FCCP FHOPA
HOPA President (2020–2021)
Clinical Associate Professor, University of Florida College of Pharmacy
Assistant Director, Experimental Therapeutics, University of Florida Health Cancer Center
Gainesville, FL

As we move into September, I think of this quotation from Henry David Thoreau: “One must maintain a little bit of summer, even in the middle of winter.” I hope that you and your family had the opportunity for some relaxation this summer and that you’ ll be able to enjoy the outdoors and observe the colorful autumn foliage despite the challenges of COVID-19.

Member Activity
Our organization was very active in advocacy efforts this past spring. I want to recognize specifically the activity of the Public Policy Committee. Members of this group collaborated with the pharmacy community on the Joint Policy Recommendations to Combat the COVID-19 Pandemic, participated in two meetings with the U.S. Food and Drug Administration/Center for Drug Evaluation and Research regarding COVID-19, met with representatives of the Centers for Medicare and Medicaid Services regarding pharmacists and COVID-19 testing and billing, promoted the addition of pharmacists in the Student Loan Forgiveness for Frontline Health Workers Act (H.R 6720), worked with the Pharmacy Health Information Technology Collaborative to support pharmacists in connection with the 2021 and 2022 Medicare Advantage and Part D Proposed Rule (CMS-4190-P) on telehealth, and created and disseminated an oncology drug shortage survey to our membership. The board is immensely grateful for the efforts of the Public Policy Committee and to HOPA staff member Dominic Sawaya and advocacy consultant Jeremy Scott.

This summer we were unable to gather in person at the American Society of Clinical Oncology (ASCO) annual meeting, but through the virtual format we were able to sift through the abundant information on the valuable efforts of oncology pharmacists. Shannon Hough presented on the efforts of several oncology pharmacists at the University of Michigan in leading a remote care monitoring program for patients with chemotherapy-induced nausea and vomiting. The team’s collaborative efforts led to a significant reduction in urgent care visits associated with nausea. Also, an abstract from PGY-1 resident Amin Virani reported that the interventions provided by an oncology pharmacist in a myeloma clinic were associated with a predicted annual value of $757,000. It is wonderful to see the value of the oncology pharmacist presented on national and international platforms.

Virtual Practice Management Program
Speaking of venues promoting the activities of oncology pharmacy, we hope your fall plans included joining us on September 11—just about the time this newsletter reaches your mailbox—for the eighth annual HOPA Practice Management program, to be held as a virtual meeting this year. Our Practice Management Program Committee has been busy converting our traditional meeting into a virtual format to accommodate our members’ needs. This program features a presentation on quality- and value-based strategy, practice pearls sessions, and a panel discussion on oncology systems. As all are aware, COVID-19 has dramatically changed the landscape of health care; this meeting will give oncology pharmacy managers and directors the opportunity to discuss their experiences during these challenging times. Additional educational content on practice management will be released following the 1-day meeting and also presented at HOPA's 2021 Annual Conference.

Looking Back, Looking Forward
HOPA members, committees, and task forces continue to be energetically engaged in activities outlined in our new strategic plan (2020–2023). The HOPA board wants to thank you again for your service to the organization, particularly during these unusual times. These groups have also observed our ongoing transition to a new management company. The decision to end our relationship with Association Management Center (AMC) was not easy: HOPA and AMC have had a longstanding partnership that has led to the growth of the organization and many meaningful relationships between staff and volunteers. The board would like to recognize the efforts and leadership of Steve Smith, AMC’s CEO, and Stacy Sochacki, who has served as HOPA’s interim executive director. Stacy has been a tremendous asset to the organization in providing guidance on strategy and governance. She has fostered a positive culture with the staff and has been essential in our work toward a seamless transition in the past several months. Another person I would like to recognize is Sarah Tiwana, HOPA’s director of operations. There isn’t enough room on this page for the positive adjectives that describe Sarah’s impact on HOPA during the past several years. I would encourage volunteers to communicate with these individuals and thank them for their service to HOPA.

Starting on October 1, HOPA’s management company will be Executive Director Incorporated (EDI) in Milwaukee, WI. EDI is one of the top association management companies in the United States, providing counsel and management for 35 national and global medical, health, and scientific associations and certifying bodies. Tara Withington, vice-president of EDI and current executive director for the Society for Immunotherapy of Cancer, has been working with AMC leadership on this transition. At the time of writing, the new HOPA team is being recruited. Announcements about the addition of key personnel will be made at a future time.

HOPA now has more than 3,650 members, and approximately 300 members participate on HOPA committees and task forces. The next chapter for HOPA is about to begin. The board hopes you share our enthusiasm and energy for our future! Much promise lies ahead. 

Pharmacist-Led Oral Oncology Programs

Oral anticancer agents have become a mainstay for the treatment of both solid tumors and hematologic malignancies. However, the benefit of patient convenience comes with the challenges of nonadherence, monitoring for adverse effects, and insurance restrictions. Establishing an institutional program for oral anticancer agents allows pharmacists the opportunity to provide patient education and support through a formal process. Three well-established pharmacist-led oral oncology programs are highlighted below. The authors provide insight on the formation and structure of the program, patient flow, and lessons learned.

Julia R. Kerr, PharmD

Robert S. Mancini, PharmD BCOP FHOPA

Amanda L. Wright, PharmD

Jessie L. Modlin, PharmD

Oral Oncology Medically Integrated Dispensing Program, St. Luke’s Cancer Institute, Boise, ID

The St. Luke’s Cancer Institute Oral Oncology Medically Integrated Dispensing Program began as a pilot residency project in 2009. Through the program a small subset of oral oncology prescriptions were reviewed and processed. With improved patient access, the pilot project quickly expanded in the following year to include all providers at the five oncology clinics in the health system. The first full-time oral chemotherapy pharmacist and half-time technician were hired in 2010. Since then, the program has grown to include 4 pharmacist full-time equivalents (FTEs), 5 technician FTEs, and a 0.5 FTE nurse, who manages mail orders for patients at the largest site. Prescriptions are processed in a spoke-and-wheel distribution model.

After a treatment plan has been entered into the Epic electronic health record (EHR) software, new prescriptions are sent to the pharmacy using the software’s “Send Plan” functionality. When the new prescription is received, an electronic chart is created for each patient, as well as a tracking sheet that is used for internal pharmacy processes only. The tracking sheet contains patient demographics, prescription details for each cycle of treatment, follow-up appointments, monitoring parameters, drug interactions, dispensing logistics, and other pertinent information that is sometimes not readily available in the EHR.

The pharmacist performs a clinical review of the new prescription, and initial contact is made with the patient to confirm the plan for starting treatment. The pharmacist reviews the details related to processing specialty prescriptions, such as prior authorization, referrals to financial advocates, and insurance contracts with out-of-state specialty pharmacies.

The new prescription is then sent to the pharmacy technician, who begins prior authorization and performs an insurance benefits investigation. The process for prior authorization is completed internally—in most cases, by a technician, a pharmacist, or both. After the prescription has been approved, the technician processes a test claim with the insurance to determine the patient’s out-of- pocket cost. If the cost is unaffordable, a referral is sent to the financial advocate to review options for financial assistance or to seek a free supply of the drug directly from the manufacturer.

When the prescription is ready for processing, the pharmacist will again contact the patient to obtain consent to fill it, make arrangements to dispense the medication, and provide medication counseling. A technician will close the loop to confirm that the prescription was received. For patients whose insurance requires the use of a specific specialty pharmacy, the pharmacist will trans- fer the prescription to the specialty pharmacy and provide contact information to the patient. A referral is then sent to the provider’s primary nurse for future refills.

Daily tasks are assigned using the “All Reminders” queue in Epic. Tasks are split between pharmacists and  technicians, using standardized wording for a variety of functions that direct the staff member on what needs to be done (e.g., refill, follow up,
dispense the prescription at an appointment, give assistance on pending drugs, mail the prescription, counsel the patient).

One of the biggest challenges was the rapid growth of the program. The program currently follows an average of 550 patients. Because the program expanded much more quickly than expected, balancing FTEs and workload has been a constant struggle. The workflow was greatly improved with the expansion of pharmacist services. This was done through
another residency project in which a collaborative practice agree- ment (CPA) was developed for the reordering of oral oncology medications.

Pharmacists sign prescriptions on behalf of providers for specific adjustments outlined in the CPA. The CPA includes clinical activities such as dose rounding to the nearest tablet size; dose adjustments based on renal and hepatic function, toxicities, and specific indications; renewal of prescription refills; and ordering laboratory tests or exams recommended by guidelines. Results from the residency project showed a statistically significant improvement in the mean turnaround times for prescriptions completed per the CPA.¹ Following implementation of the CPA, it was observed that each pharmacist saves significant time each day by signing prescriptions on behalf of providers per the CPA. Further expansion of pharmacist services is under consideration, given the success of the CPA in this program. Some of the barriers encountered include insurance contracting, with many insurers still requiring contracted specialty pharmacies, and obtaining access to dispense products from pharmaceutical manufacturers. Fortunately, the program does have access to dispense the Celgene Risk Evaluation and Mitigation Strategies program drugs, and each pharmacist is a certified counselor. Since the launch of the pilot project, the
program has published more than a dozen peer-reviewed articles and has been referenced by the 2018 Hematology/Oncology Pharmacy Association’s oral oncolytic therapy practice standard² and the Standards for Medically Integrated Dispensing produced jointly by the American Society of Clinical Oncology and the National Com- munity Oncology Dispensing Association.³ In addition, the program has won a medication safety award from the American Society of Health-System Pharmacists (2012) and two innovator awards from the Association of Community Cancer Centers (2011 and 2020). The pharmacy department continues to expand and refine the delivery of patient services in its Oral Oncology Medically Integrated Dispensing Program.

References

1. Wright AL, Matta SF, Kerr JR. Expansion of pharmacist practice in oral oncolytic therapy with a collaborative practice agreement. J Oncol Pharm Pract. 2020; 1078155220905004 [published online ahead of print February 19, 2020]. doi:10.1177/1078155220905004
2. Mackler E, Segal EM, Muluneh B, Jeffers K, Carmichael, J. 2018 Hematology/Oncology Pharmacist Association best practices for the management of oral oncolytic therapy: pharmacy practice standard. J Oncol Pract. 2019;15(4):e346-e355. Available at https://ascopubs.org/doi/10.1200/JOP.18.00581
3. Dillmon MS, Kennedy EB, Anderson MK, et al. Patient-centered standards for medically integrated dispensing: ASCO/NCODA standards. J Clin Oncol. 2020;38(6):633-644.

Oral Anti-Cancer Agent Management Clinic, Malcom Randall VA Medical Center, Gainesville, FL

Kourtney LaPlant, PharmD BCOP

Paige May, PharmD BCOP

Ashley McGee, PharmD MBA BCOP

When the shift from intravenous (IV) to oral anticancer agents
began around 2008, concerns about proper utilization and toxicity management surfaced. It was recognized that these patients needed to be properly taught how to take the medications, what the common toxicities were and how to manage them, and when to call for help. The oncology pharmacy staff (three full-time oncology pharmacy specialists) at the Malcom Randall VA Medical Center in Gainesville, FL, approached the oncology physician leadership for a discussion of how the pharmacy staff could assist in managing this patient population.

Leadership buy-in from both the medical oncology and the phar- macy administration is likely the first hurdle of any proposed new clinic. Our oncology leaders were enthusiastic about a pharmacy-led initiative to support patient care. From a pharmacy standpoint, concerns are usually related to staffing. Are there enough hours to devote to clinical activities and still support oncology operations? In an examination of support staffing, we identified the availability of two advanced-practice pharmacy interns per month and several pharmacy residents who were doing oncology rotations and saw a learning opportunity. The idea of using trainees helped us obtain support from the pharmacy leadership, and our plan was bolstered by published research on the potential cost benefits of ensuring appropriate use of these high-cost drugs.^1,2

Referral to the clinic begins when pharmacy staff are notified through a consultation with oncology providers of the desire to start a patient on oral anticancer agents. The pharmacist reviews the patient’s record to ensure that the patient meets the criteria for the use of a given drug. If therapy is determined to be appropriate, a member of the pharmacy team will counsel the patient. In-person counseling is preferable, but video visits or phone calls are acceptable. Pharmacy trainees are educated by oncology pharmacists before they conduct patient education, to ensure their competency. After a patient has been counseled, a weekly follow-up phone or video call is scheduled with pharmacy for the first 3 weeks until the patient returns to the clinic in the fourth week (for monthly regimens). The oncologist orders the anticancer therapy, but the pharmacy staff's scope of practice within federal law and institu- tional credentialing procedures allows them to order supportive care medications, depending on the medication’s toxicity profile.

Pharmacy trainees, when available, conduct most of the follow-up visits, using a templated toxicity assessment form (the form has been previously published in a more comprehensive review of our clinic³). The pharmacist then develops a plan for any needed toxicity management and implements any changes to the drug therapy. Additional supportive care medications, monitoring devices such as blood pressure monitors, and lab tests can be ordered by the pharmacist if necessary. If changes to the anticancer therapy regimen are needed, pharmacy staff will instruct patients to withhold their medication and will contact the provider to discuss the plan, making changes as needed.

Following the initial month (which we felt to be the most crucial period for ensuring compliance), the responsibility for follow-up is returned to the oncology provider. Pharmacy may be asked to conduct additional interim follow-up on certain issues. Institutional policy calls for monthly visits and labs for the first 6 months when a patient is taking a new medication. An oncology pharmacy staff member reviews the patient’s labs before processing each refill. We are also field testing a population management tool to help track patients on oral chemotherapy agents and identify patients who are overdue for refills, may have abnormal labs, or may have been lost to follow-up. After a patient has been stable on one dose for 6 months, up to two refills are allowed. If a patient is stable on a dose for a year or more, 6-month follow-up may be considered on a case-by-case basis.

The pharmacy-led oral chemotherapy management clinic has been operating since 2009. One lesson learned in the beginning was the importance of formally establishing proper follow-up to help ensure accountability. Adaptations have included increasing the clinical time devoted to management of oral anticancer agents and incorporating video follow-ups to allow for visual assessment of skin toxicities and overall improvement of patient assessment capabilities. As the use of oral anticancer agents continues to expand and evolve, we see a continued future for the clinic. Future directions, if staffing allows, could include the use of oncology phar- macy specialists to conduct follow-up (in lieu of a physician visit) for stable patients receiving oral chemotherapy.

References

1. Goodin S, Griffith N, Chen B, et al. Safe handling of oral chemotherapeutic agents in clinical practice: recommendations from an international pharmacy panel. J Oncol Pract. 2011;7(1):7-12. doi:10.1200/jop.2010.000068
2. Mancini R, Wilson D. A pharmacist-managed oral chemotherapy program: an economic and clinical opportunity. Oncol Issues J. 2012 January/ February;27(1):28-31. https://doi.org/10.1080/10463356.2012.11883635
3. May P, LaPlant K, McGee A. Practice model: establishing and running an oral chemotherapy management clinic. Asia Pac J Oncol Nurs. 2017;4:299-303.

Comprehensive Oral Chemotherapy Management Program, University of North Carolina, Chapel Hill, NC

Benyam Muluneh, PharmD BCOP CPP

Since the World Health Organization released its landmark analysis of medication adherence, “Evidence for Action,” in 2003, the approval of oral chemotherapy drugs (OCs) has exploded.¹ In the wake of that explosion, patients’ nonadherence to taking OCs has become a significant barrier to achieving clinical outcomes, creating an opportunity for clinical pharmacy services.² For that reason, we implemented our comprehensive OC management program at the University of North Carolina in 2014.

Our first step was to survey 95 patients to understand the patient-perceived barriers to adherence.³ We found that 30% of respondents forget to take their OC as prescribed, and 21% of patients deliberately cut back on their OC primarily because of adverse effects or specialty pharmacy delays.³ Subsequently, we established an OC management program with an embedded clinical pharmacist and our own specialty pharmacy. We hypothesized that a closed-loop system where patients received their OCs from an institutional pharmacy would yield better adherence, provide better access, and be financially viable.

Our program is structured to ensure that our clinical pharmacists are involved throughout the continuum of the patients’ care. Patients receive education on their OC from a pharmacist after a referral is made by the oncologist. Clinical pharmacists are stationed in the clinic, facilitating a seamless (often informal) referral process. The education encounter contains a comprehensive medication review, discussion of common and serious adverse effects and the importance of medication adherence, and an explanation of the drug access process. The majority of prescriptions are sent by physicians (MDs), nurse practitioners (NPs), and physician assistants (PAs), but clinical pharmacists also occasionally prescribe, as permitted through the Clinical Pharmacist Practitioner licensure by the North Carolina Medical Board. A limited number of refills are given, and patients are followed closely by both specialty and clinical pharmacists for adverse effects.

Initially, patients have frequent visits with the clinical pharmacist so that toxicities from the new OC and adherence can be assessed. Typically, a pharmacist encounter (telephone or in-person) occurs at 2 weeks and 4 weeks after the patient starts the OC. The patient is also often seen by the MD (or NP or PA)  at the 4-week visit; the patient’s time with the clinical pharmacist is scheduled first. This allows the pharmacist to address OC-related concerns so that the MD, NP, or PA can focus on follow-up of disease status. A satisfaction survey of our physicians showed that they appreciated the involvement of the pharmacist in this follow-up approach.⁴

Based on the first 3 months of treatment, patients are given a more intensive or a less intensive follow-up plan. Patients who have a medication possession ratio <80%–90%, who experience adverse drug reactions or have abnormal laboratory values, or who have an MD request for more frequent follow-up are followed closely with pharmacist visits every 1–2 weeks. Patients deemed to be at lower risk of nonadherence (not falling within any of the high-risk parameters) would have a visit with the pharmacist every 3–6 months while they were on therapy.

Our comprehensive OC management program improved patient outcomes. During the first 10 months, 107 patients were enrolled, for a total of 350 pharmacist encounters during which 318 adverse events were reported and 235 interventions were implemented. We observed increased rates of patient understanding of OCs, high rates of adherence, and high rates of patient and provider satisfaction. In addition, major molecular response rates increased in our chronic myeloid leukemia patients compared with those in our historical control (pre: 58% vs. post: 83%).⁴

After implementation, we faced notable challenges in ensuring the sustainability of the program. First, because pharmacists were embedded in the clinic, they became core members of the clinical team and were addressing not only concerns with OC, but also concerns about supportive care, anticoagulation, transitions of care, infectious complications, and more. This expanded field of responsibility may have contributed to less intensive follow-up of patients on OC in some clinics. The continued increase in the approval of OCs also makes it challenging for the clinical pharmacy staff to own the entire drug-access program. Our institution has therefore embedded disease-specific medication access specialists who work alongside clinical pharmacists to expedite prior authorizations and applications for copay assistance. Significant challenges have also occurred with reimbursement and contracting. Unfortunately, limited distribution models sometimes prevent our pharmacy from serving our own patients.⁵ To deal with this problem, staff members are currently developing a more comprehensive workflow addressing the needs of patients who have their drugs filled through external channels.

Overall, implementation of a structured OC management program has yielded positive clinical, humanistic, and financial outcomes for our patients. We continue to modify our internal processes in order to adapt to the increasing number of OC approvals and a challenging limited-distribution landscape. 

References

1. Burkhart PV, Sabaté E. Adherence to long-term therapies: evidence for action. J Nurs Scholarsh. 2003;35(3):207.
2. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28(14):2381-2388.
3. Muluneh B, Deal A, Alexander MD, et al. Patient perspectives on the barriers associated with medication adherence to oral chemotherapy. J Oncol Pharm Pract. 2018;24(2):98-109.
4. Muluneh B, Schneider M, Faso A, et al. Improved adherence rates and clinical outcomes of an integrated, closed-loop, pharmacist-led oral chemotherapy management program. J Oncol Pract. 2018;14(6):e324-e334.
5. Savage SW, Bates JS, Muluneh B. Challenges continue for true patient-centered access. 2016. Pharmacy Times. June 2, 2016. https://www.pharmacytimes.com/publications/specialty-pharmacy-times/2016/June-2016/Challenges-Continue-for-True-Patient-Centered-Access

Off the Beaten Path

Gary C. Yee, PharmD FCCP
Associate Vice Chancellor for Academic Affairs
Professor of Pharmacy Practice and Science
University of Nebraska Medical Center
Omaha, NE

Growing up in the Pacific Northwest, I would sometimes hike the many trails in the area. I enjoyed the solitude and the time to reflect. That love for the outdoors continues today, and one of our family’s favorite vacation activities is to go on a hike, particularly one that leads to a beautiful scenic spot. One of the most memorable (and difficult) hikes was Angel’s Landing in Zion National Park in Utah. I didn’t fully appreciate the beauty of the mountains and water until I moved away.

A long career is like a long hike. You never know exactly where the trail is going to take you. I enjoy reading the reflections of “young” practitioners in the Hematology/Oncology Pharmacy Association (HOPA) newsletter, and Susie Liewer, a former student who works at my institution, encouraged me to write one from the perspective of a “mature” practitioner. Next year, I will celebrate 40 years since the completion of my training. In this column I share a few of the lessons learned from my career. I won’t repeat many of the usual lessons shared in these columns—work hard, have a plan, never stop learning, learn from your failures, etc. They are timeless, and I agree with them.

Know Yourself

I know you hear this repeatedly, but it is not emphasized enough. We are often told to never stop learning, but we sometimes forget to learn about ourselves. Why is this so important? In the book On Becoming a Leader, Warren Bennis tells us that our assumptions (values) cause us to select certain behaviors, and those behaviors have consequences.¹ Our values are determined in part by our childhood and culture. As a proud Asian American, I have grown to accept and embrace the values of my culture. That wasn’t always the case. When I was growing up, I was embarrassed by my Chinese middle name, which according to tradition was given to me by my paternal grandfather. Then my parents told me that my name literally meant “above the crowd,” that I would be outstanding among my peers. I didn’t think too much about it at the time, but it now inspires me to strive for excellence in everything that I do. What do you care about? Take time to reflect, not just when you fail or face adversity. As a Christian, I developed a habit of regular reflection, usually during Bible study or prayer. That habit of regular reflection has helped me with every major decision.

What are your strengths? Take advantage of one of the many available tools to learn about your strengths. When I took StrengthsFinder (now called CliftonStrengths)² several years ago as part of a leadership development program at the university, I was surprised at how accurately it explained my strengths.

Expect the Unexpected

Trails can take unexpected turns. It’s great to have a plan and goals. When I was an undergraduate pharmacy student, I worked in a cancer research laboratory and liked it. I later realized that I liked research because I was analytical and enjoyed solving problems (I played chess in high school and competed in state and national tournaments). When I completed my Doctor of Pharmacy degree, oncology pharmacy was an emerging specialty, and few role models existed. Even fewer specialty residencies (most were referred to as fellowships) were available. I was fortunate to have great mentors such as Bill Evans who inspired me to dream big. I wanted to have my own laboratory supported by research grants. I wanted to publish in the very best medical journals. Things started well, and I was on track to meet my goals. Then the unexpected happened—twice. In each case, key physician collaborators and mentors moved, and my research program was adversely affected. My plan and goals were shattered. Reflection is important during times of disappointment. I remember feeling like a failure and wondering what I was going to do. One of the important lessons learned during those times was that what I did (as an oncology pharmacist, a professor, a researcher)—my professional identity—did not define who I was (a person, a husband, a father, and now a grandfather).

During a long career, unexpected events will occur, and some will have a personal impact. It could be a change in leadership or your responsibilities. It could be a larger global event such as the COVID-19 pandemic. Many will be outside of your control, but some could also be the direct result of something you said or did. You will be disappointed and may feel like a failure. Adopt a growth mindset. Be thankful for those difficult times; learn from them, and don’t let them define who you are.

Explore New Paths

Don’t be afraid to explore a new path. Shortly after returning from a 1-year sabbatical, I decided to pursue a department chair position in a college of pharmacy. My decision surprised others because I had stated earlier that I had no desire to be an administrator. I wanted to make a difference by helping and mentoring others. After serving in that position for about 7 years, I decided to step down and return to the faculty. About 2 years later, I was asked by our new dean to become an associate dean. Between my time as department chair and associate dean, I reflected on what I wanted to do in the last chapter of my career. I decided to improve the profession through service in professional organizations. Service has always been part of my DNA, but I was so focused early in my career that I didn’t actively pursue service opportunities. Since that time, I have served on the HOPA Board of Directors, the American College of Clinical Pharmacy (ACCP) Board of Regents (as president), and the ACCP Research Institute Board of Trustees. I currently serve on the Board of Pharmacy Specialties Board of Directors.

After serving as associate dean for about 10 years, I decided to step down because I wanted to do something different. While the college recruited for my replacement, the position of associate vice chancellor for academic affairs became available at my institution. I wasn’t ready to retire, so I reflected on whether to pursue this new opportunity. I enjoyed academic administration and saw this as an opportunity to get out of my comfort zone and learn new skills. I decided to apply and accepted the position in July 2019. After nearly 1 year into my new position, I can say that the change has been positive. It is always uncomfortable doing things for the first time, but I have learned so much from that experience. And I am able to continue to teach and interact with pharmacy students, residents, and faculty.

In contrast to our parents or grandparents, few of us will do the same thing in the same institution for several decades. I could have remained in my associate dean position until retirement. During your career, you will know when it is time for a change. It is different for every person, but for me, it was persistent feelings of restlessness and lack of peace. It usually occurred after about 7–10 years in my position. The timing reminds me of Simone’s Maxims, based on a Grand Rounds presentation at MD Anderson Cancer Center.3 Dr. Joe Simone was a pediatric oncologist and senior administrator at several major academic medical centers, including St. Jude Children’s Research Hospital, Stanford University Medical Center, and Memorial Sloan Kettering Cancer Center, and most recently at Huntsman Cancer Center. Although he gave his presentation more than 20 years ago, his comments are just as relevant today. In his article, Dr. Simone states that “with rare exceptions, the appropriate maximum term for an academic leader/administrator is 10 years, plus or minus 3 years.”³

Exploring new paths can be scary. When I decided to step down, I didn’t have a backup plan, although I knew I still had a satisfying job (one of the advantages of being a tenured professor). Leslie Hendeles, a former colleague at the University of Florida, used to say that being a professor was the best job in the world. And I knew that I was the same person regardless of my position title.

Enjoy the journey. And don’t forget to stop and smell the roses. 

References

1. Bennis W. On Becoming a Leader. 4th ed. New York, NY: Basic  Books; 2009.
2. CliftonStrengths, Gallup website. https://www.gallup.com/cliftonstrengths/en/home.aspx. Accessed June 2, 2020.
3. Simone JV. Understanding academic medical centers: Simone’s Maxims. Clin Cancer Res. 1999;5:2281-2285.

Leadership Strategy During Challenging Circumstances: Lessons from a Roman Emperor

Amanda Brahim, PharmD BCOP BCACP BCPS
Clinical Pharmacy Manager
Memorial Cancer Institute
Pembroke Pines, FL

Jameshia Below, PharmD
PGY-2 Oncology Pharmacy Resident
Memorial Cancer Institute
Pembroke Pines, FL

Dorinda Segovia, PharmD
Vice President – Pharmacy Services
Memorial Healthcare System
Pembroke Pines, FL

Leading a healthcare team is inherently challenging because of the many complex, high-risk tasks and competing priorities involved and the rapidly evolving changes to our landscape. Now imagine the stakes being amplified during times of adversity, when situational outcomes are dependent on the key tactics we employ in response to challenging circumstances. Some of the most successful strategies are encompassed in what is known as Stoic leadership.

Stoicism is an ancient Greco-Roman philosophy founded in the fourth century BC, and its principles can be applied to our personal and professional lives. Stoicism teaches us how to keep a calm and rational mind no matter the circumstances and to focus on what we can control, rather than letting events outside our control dominate our actions.

The Roman emperor Marcus Aurelius, the last of the five great emperors, ruled from 161 to 180 AD. The most powerful man in the world at the time, he was a stout proponent of Stoic philosophy and was renowned for his humanistic, level-headed leadership. He recorded his thoughts and observations in a journal, now known as Meditations.¹ These journal writings have inspired some of the greatest leaders in history. Stoicism gave Aurelius a guidebook for living a virtuous life, focusing on what mattered, and persevering despite setbacks—and he had quite a few during his reign. It was a time of impending wars; famine; threats to the throne; and, most relevant to us in this day, the Antonine Plague. This pandemic spanned the Roman Empire, persisted for 15 years, and claimed approximately 5 million lives in Europe. Yet this period was also a time of an expansion of power for the Roman Empire largely because of Aurelius’s leadership during adversity. Marcus Aurelius faced unprecedented challenges head on, with total composure and endurance.

Recently, our healthcare community has experienced challenges strikingly similar to those faced by the Romans more than 2,000 years ago. The COVID-19 pandemic tests our resilience daily. With restricted resources, conflicted governmental leadership, and limited relevant experience, we have battled a virus with the potential to cause mass casualties. As leaders, we control our response and set the stage for how others respond to adversity. Similar to Aurelius, by using the tenets of Stoicism, such as setting priorities, taking decisive action, and adapting and planning for the future, we are able to persevere during challenging times.

Setting Priorities

“If you seek tranquility, do less. Or (more accurately) do what’s essential. Do less, better. Because most of what we do or say is not essential.”—Marcus Aurelius, Meditations¹

Leaders face various sources of pressure that threaten to pull their attention in different directions. It takes skill to separate the distractors from the priorities. It is crucial to focus your energy on tasks that move your team forward, on what Aurelius called “the essential.” When you begin doing that, you are much more likely to hit your goals.

In our health system, it was determined that these things would be our priorities during the COVID-19 pandemic:

• minimizing disease spread and transmission to patients, healthcare personnel, and the community
• maximizing efficient use of resources, including staff, personal protective equipment (PPE), and medications
• maintaining the highest level of care, quality, and service for our patients and families.

Our primary tactic to achieve these goals was to accelerate the transition of digitization and automation. Fortunately, we were able to leverage our previously implemented telehealth platform enabled by our electronic medical record (EMR) system in selected areas within our system. The rapid expansion of that platform to include all oncology providers required the building of new appointment types and clinic schedules in the EMR and a massive preparation of devices and the physical space where the visits would occur. Physicians and staff had to be trained, and new workflows were created and implemented in an extremely short timeframe.

Our hospital system implemented large-scale community drive-through testing in collaboration with the National Guard. Staff members were retrained to provide testing and support the community. As the need for flexible space escalated, we converted conference rooms and other spaces to allow for additional capacity.

With physical-distancing recommendations in full effect, we still needed to maintain accurate medication histories and reconciliation services. We implemented a medication reconciliation call center to limit face-to-face interactions. By using an open flow of communication and collaboration, this method allowed pharmacy technicians to assess patients in the emergency department and on COVID isolation units without additional exposure risk. The leadership, physicians, and information technology and care teams collaboratively tackled this challenge with expedience, knowing that they were helping us care for our patients while protecting our teams.

Taking Action

“You have power over your mind—not outside events. Realize this, and you will find strength.”—Marcus Aurelius, Meditations¹

This is the most prominent principle in Stoic leadership. There are things we control and things we don’t. We should focus on the things we control, devoting our energy and actions to them. Identifying areas that we can control allows us to begin making plans, taking into account the multitude of possibilities justified by current evidence. Action requires courage, not brashness—creative application, not brute force. We need to act with deliberation, boldness, and persistence.

We researched our decisions meticulously, taking note of experiences in other parts of the world. We examined best practices as well as cautionary tales to devise the best approach. With flexibility, we relied less on traditional organizational structures and started locking in practices that sped up decision making and execution during the crisis.

We took action by forming systemwide collaborative groups, each with a specific purpose. A multidisciplinary infectious disease work group composed of physicians and pharmacists designed and continuously updated treatment algorithms. Criteria for the use of interleukin-6 inhibitors were developed in collaboration with cellular therapy teams, who were familiar with cytokine release syndrome. Another systemwide task force was initiated to maintain adequate inventory of PPE and critical drugs and help coordinate care between campuses, including patients’ access to newly initiated clinical trials.

Oncology patients were stratified into three categories: those who had life-threatening conditions that required immediate treatment (e.g., newly diagnosed acute leukemia patients), patients with serious conditions for whom treatment was not urgent but could not be delayed until the end of the pandemic (e.g., breast cancer patients undergoing active treatment), and patients with a disease stage for which treatment could wait until the pandemic subsided without adversely affecting outcomes (e.g., those in long-term follow-up). Each group was assigned appropriate levels of care based on the risk category. Our stem cell transplant program conducted a similar assessment, deferring consolidative transplant for conditions such as multiple myeloma. By setting priorities in patient management and system strategies, we were able to limit interruptions in patient care while mitigating risks.

Communication

A low-key, practical, and democratic communication style is crucial in times of adversity. Throughout his Meditations, Aurelius promoted the belief that no matter what happens, individuals should maintain control of the mind at all times, giving thought to the consequences of their words instead of reacting to their impulsive natures.¹ Effective communication during times of crisis is powerful because it reduces emotional distress caused by the unknown, provides tactical guidance, and demonstrates to team members that their leaders are genuinely concerned and involved in the situation.

Our institution implemented team huddles regarding workflow changes, resources, inventory management, treatment guidelines, staffing, and daily assignments, using a variety of communication channels. The system’s chief nursing officer sent out a daily Coronavirus Watch Board e-mail that included the current numbers of active cases, persons under investigation, mortalities, and discharges. The Watch Board communication also reported on the status of PPE supply, current guidelines regarding patient flow, masking protocols, etc. Communicating in a consistent, transparent manner was instrumental in maintaining the proper flow of information and getting necessary initiatives implemented.

A systemwide focus on communicating how we were keeping our team members safe was maintained. In several areas of the country, large numbers of front-line healthcare employees were infected. Reassuring our team, especially our front-line staff, that their safety was a top priority created a culture of camaraderie. Having this trust between leaders and team members is crucial during difficult times. Team members who feel that they are valued and appreciated will seek to provide high-quality work and find solutions to obstacles that may arise.

Turning Obstacles into Advantage

“The impediment to action advances action; what stands in the way becomes the way.”—Marcus Aurelius, Meditations (Book 5.20)¹

Massive changes such as those associated with the novel coronavirus could and should foster the strengthening of key values like collaboration, flexibility, inclusion, and accountability. We needed to continue to deliver service as usual, but in the most unusual of circumstances. We needed to be open to frequent and constant change in order to operationalize services as new information became available—thus forcing us to evolve our means as a consequence of rapidly morphing events. The need to operate differently gave our organization the opportunity to grasp new opportunities, embrace never-before-thought-of abilities, and expand our horizons and operations beyond previous limitations.

Newfound ideas that previously may not have been considered became a way of the future. Innovative ideas implemented in our system included new services, telephonic medication histories, patient counseling, and telepharmacy appointments and consultations. We also adjusted the operating hours of our dispensing pharmacy to be more convenient for patients. Our community pharmacy service line implemented home and mail delivery and developed a way to offer curbside pickup. This not only kept our volumes steady (we expanded ways to deliver our offerings for the meds-to-beds program) but also minimized potential COVID-19 exposure to discharged patients.

Planning for the Future

“Let no one rob me of a single day who is not going to make me an adequate return for such a loss.”—Seneca (Roman Stoic philosopher), On the Tranquility of the Mind, 1.11b²

Health care may never be the same again. However, we cannot let our short-term focus distract us from our long-term vision and plans, and we can’t dismiss the opportunity to capitalize on lessons learned.

One must plan and prepare for unexpected events. As we build new facilities, the experience of needing social distancing will enable us to think beyond what we know today and work on improving our emergency-preparedness through design, construction, and strategy development. Risk stratification, the development of new services, the removal of barriers, and shifts to telehealth will remain permanent tactics for facilitating access to care. The learnings regarding the importance of open communication and teamwork must pave the way for a higher-functioning system, making a better return on the time spent managing recent events.

Conclusion

Leadership during times of adversity can teach us about the types of leaders we want to be, no matter the circumstances. Leaders—with their own unwavering focus—must motivate others to see the tough times through, not just navigate through calm waters. As any crisis transitions from its urgent phase, the time pressure will ease, as will the need for split-second decisions. At that point, the plan must evolve into a more complex system that looks at recovery and getting things back to normal—whatever the new normal looks like.

An important tenet of Stoicism is that time must not be wasted and every day must be lived as though it is one’s last. Each day is a new opportunity to make a lasting impact. Maintaining this mindset helps us guide others to accomplish a shared vision. By paying attention to our own emotions, needs, and behaviors, we will be better prepared to handle times of crisis. Consequently, we will be more capable of containing the impact of a crisis, regaining control, and effectively preventing, or reducing the duration of, an extremely difficult leadership situation.

References

1. Marcus Aurelius. Meditations (trans. G. Hays). New York, NY: Modern Library; 2002.
2. Seneca. On the Tranquility of the Mind (trans. A. Stewart). 1900; independently published in 2017.

Making an Impact: Research Highlights from Recipients of the First Annual Certificate of Recognition for Exemplary Research on Quality of Care in Oncology

Nan Limvorasak, PharmD BCOP
Pharmacy Program Coordinator
Cedars-Sinai Medical Center
Los Angeles, CA

Amy H. Seung, PharmD BCOP FHOPA
Senior Medical Director
Pharmacy Times Continuing Education
Ellicott City, MD

The Quality Oversight Committee of the Hematology/Oncology Pharmacy Association (HOPA) would like to congratulate the recipients of the first annual Certificate of Recognition for Exemplary Research on Quality of Care in Oncology. A work group of the committee developed an evaluation process and reviewed each of the completed research and trainee research abstracts. Criteria for evaluating the submitted abstracts included the focus of the research on quality and value metrics in the care of patients with cancer using a nationally recognized oncology or pharmacy quality metric and the potential impact of the results on current practice.

Four certificates were awarded for abstracts presented at the HOPA Ahead 2020 conference in Tampa, FL: one was for completed research by Rachel McDevitt, PharmD BCOP (University of Michigan Rogel Cancer Center); and three were for trainee research by Jacqueline Majeski, PharmD (Maine Medical Center); Bianka Patel, PharmD (University of North Carolina Medical Center); and Michelle Azar, PharmD candidate (Michigan Oncology Quality Consortium and University of Michigan).

Evaluation of an Oncology Transitions of Care Pilot Program, presented by Rachel McDevitt, PharmD BCOP

Transition-of-care coordination led by pharmacists has been associated with a decrease in patient readmissions and an improvement in quality of care; however, implementation has been a nationwide challenge, and oncology patients are often excluded from these programs. To further study the feasibility of implementing such a program for patients with cancer, McDevitt and colleagues conducted a 3-month pilot program to investigate the effectiveness of an oncology pharmacist-led transition-of-care program on clinical outcomes at hospital transitions.¹ Of the 29 patients enrolled, 15 patients received outpatient pharmacist follow-up, and 14 patients did not. A total of 42 interventions were observed in a group of 15 patients with gastrointestinal cancers enrolled in the intervention cohort. The most common action items were related to symptom management, antibiotics, oncologic treatment, issues related to other comorbidities (e.g., diabetes), diet, anticoagulation, and medication reconciliation. In this prospective study, the 30-day readmission rate was reduced by 50% for patients who received outpatient pharmacist follow-up compared to patients who did not receive follow-up. Given the successful establishment of the program at the current institution, expansion to other oncology specialties is planned.

Impact of a Pharmacist Managing Outpatient Oral Oncolytics, presented by Jacqueline Majeski, PharmD

Oncology pharmacists have been instrumental in providing high-quality care to patients with cancer. In multidisciplinary teams, their role has expanded from providing patient education to leading clinically meaningful interventions measured by various quality metrics including symptom improvement, clinical outcomes, and patient satisfaction.² Now greater opportunities exist for pharmacists to enhance care through interprofessional collaboration.

Majeski and colleagues evaluated the impact of having a pharmacist managing outpatient oral oncolytics. They reported that pharmacists’ involvement in managing oral cancer therapy had a positive impact on the quality of patient care, as shown in a retrospective chart review.³ Their primary objective was to assess adherence to the 2016 American Society of Clinical Oncology (ASCO)/Oncology Nursing Society Chemotherapy Administration Safety Standards for oral oncolytics in a pharmacist-led oral oncolytic management program. A total of 193 interventions were made on 96 oral prescriptions, of which 45% involved dosing recommendations. The most common interventions involved medication procurement assistance. The results showed greater opportunities related to preventing prescribing errors and promoting patient safety and further highlighted the impactful interventions of oncology pharmacists.

Characterization of Testing for Targeted Therapy in Advanced Non–Small Cell Lung Cancer (NSCLC), presented by Bianka Patel, PharmD

Oncology pharmacists are increasingly being integrated into precision medicine programs to identify actionable mutations and apply specific targeted therapies to treat cancer.⁴ The service that they provide in this area demonstrates the important role of pharmacists in personalized medicine and opportunities for their integration. The completion of molecular testing and testing turnaround time (TAT) for patients with stage IV NSCLC with adenocarcinoma histology are included as metrics in ASCO’s Quality Oncology Practice Initiative (QOPI) recommendations.

To assess TAT for molecular testing, Patel retrospectively reviewed patients with stage 4 NSCLC with adenocarcinoma histology and identified 66 patients.⁵ Testing was completed in most patients (89.4%). The median time from diagnosis to receipt of sample at the vendor was 13 days, and the median time from vendor’s receipt of sample to testing results was 13 days, which exceeded ASCO QOPI recommendations that test results be available within 10 working days. The most common reasons for prolonged TAT were delays in samples being sent to the vendor and insufficient tissue samples. Results from this study identified specific opportunities for process improvement to be consistent with published guidelines. The authors made several recommendations for improvement of TAT, including the use of reflex molecular testing at the time of diagnosis and measures to ensure adequate sample quality.

Statewide Quality Improvement Addressing Overutilization of Neurokinin-1 (NK-1) Receptor Antagonists, presented by Michelle Azar, PharmD candidate

QOPI became available to ASCO members and their practices in 2006, with the goal to assess practice performance for a series of evidence- and consensus-based process measures.⁶ Practices that participated in QOPI demonstrated improved performance in self-reported process measures, with the greatest improvement demonstrated in initially low-performing practices.⁷ Symptom management, including the appropriate use of antiemetic therapy, is one of the medication-related QOPI measures. The use of NK-1 receptor antagonists or olanzapine administered for low or moderate emetic risk is classified as one of the top five test measures in QOPI. To evaluate this metric, Azar and colleagues conducted a statewide quality improvement evaluation addressing overutilization of NK-1 receptor antagonists.⁸ Following development of a framework for assessing the lack of concordance with guidance recommendations, a survey was developed to gain an understanding of the patterns of usage. Education on chemotherapy-induced nausea and vomiting was provided to participating practices, with the goal of decreasing inappropriate NK-1 receptor antagonist usage to less than 30%. The state average in fall 2018 was 34% and decreased to 19% in spring 2019, compared to the national average of approximately 29%. Reassessment of practice performance is planned following program completion. This study further demonstrated an opportunity for improvement through the use of prepopulated antiemetic order sets and evidence-based education led by oncology pharmacists.

The four recipients of the inaugural certificate of recognition addressed quality in cancer care using validated quality metrics, and their research further supports the roles of oncology pharmacists. 

References

1. McDevitt R, et al. Evaluation of an Oncology Transitions of Care Pilot Program. HOPA 2020 annual conference, Tampa, FL. Abstract PM10.
2. Mackler E, Segal EM, Muluneh B, et al. 2018 Hematology/Oncology Pharmacist Association best practices for management of oral oncolytic therapy: pharmacy practice standard. J Oncol Pract. 2019;15: e346-e355.
3. Majeski J , et al. Impact of a Pharmacist Managing Outpatient Oral Oncolytics. HOPA 2020 annual conference, Tampa, FL. Abstract TR147.
4. Walko C, Kiel PJ, Kolesar J. Precision medicine in oncology: new practice models and roles for oncology pharmacists. Am J Health Syst Pharm. 2016;73:1935-1942.
5. Patel B. Characterization of Testing for Targeted Therapy in Advanced Non-Small Cell Lung Cancer. HOPA 2020 annual conference, Tampa, FL. Abstract TR174.
6. Jacobson JO, Neuss MN, McNiff KK, et al. Improvement in oncology practice performance through voluntary participation in the Quality Oncology Practice Initiative. J Clin Oncol. 2008;26:1893-1898.
7. Neuss MN, Malin JL, Chan S, et al. Measuring the improving quality of outpatient care in medical oncology practices in the United States. J Clin Oncol. 2013;31:1471-1477.
8. Azar M, et al. Statewide Quality Improvement Addressing Overutilization of Neurokinin-1 Receptor Antagonists. HOPA 2020 annual conference, Tampa, FL. Abstract TR187.

Pharmacists Bridging the Gap Between Oncology Care and Primary Care

Emily Mackler, PharmD BCOP
Director, Clinical Quality Initiatives
Michigan Oncology Quality Consortium
Ann Arbor, MI

Amy Thompson, PharmD BCACP
Director, Ambulatory Clinical Pharmacy Practices
Michigan Medicine
Ann Arbor, MI

Over the past several years cancer treatments have changed from classic cytotoxic therapies to molecular targeted treatments. With this change in target, we’ve seen more oral anticancer agents (OAAs) approved and integrated into standard treatment protocols.1 In addition to the type of systemic therapy changing, the duration of treatment has been extended. The average duration of cancer treatment in the late 1990s (1994–1999) was 4 months, with the median duration more than doubling to 9 months just a decade later (2010–2014).¹ Extending the median duration of cancer treatment, and moving to OAAs that are generally taken daily at home, increases the interaction of systemic cancer treatment and comorbid conditions caused by drug-drug interactions and potentially worsening side effects.²

Among Medicare beneficiaries age 65 years and older with cancer, 40% have at least one comorbid condition, and 15% have two or more. The most common of these comorbidities are cardiovascular disease, diabetes mellitus, and mental health disorders.² We know that cancer has effects on comorbidities—particularly related to the worsening of diabetes or cardiovascular disease seen with certain systemic therapies like tyrosine kinase inhibitors, endocrine therapy, and steroids. We also know that comorbidities can affect cancer outcomes, given their impact on treatment toxicities, treatment effectiveness, and overall survival. Given the significant proportion of patients who are managing a chronic condition in addition to their cancer diagnosis, a collaboration between oncologists and primary care providers is necessary to ensure the patient’s overall health.^2-5 Unfortunately, the literature is replete with evidence of lapses in communication between oncology specialty providers and primary care providers. These lapses provide multiple opportunities for improvements in care and, ultimately, in patient outcomes.^3,6,7

We believe that pharmacists are well suited to help bridge the gap between oncology care and primary care. Pharmacists are well versed in adverse-effect management and in identifying and resolving drug-drug interactions. Studies estimate that drug-drug interactions affect one-third of patients treated for cancer. Pharmacists can screen medication lists, assess clinical significance, and recommend alternatives. In addition, pharmacists can also recognize treatment-related adverse effects and arrange for proper management and follow-up.^8-10

In an effort to enhance the collaboration between oncology and primary care, we developed the Primary Care Oncology Model (PCOM) pilot program in the Michigan Oncology Quality Consortium (MOQC).¹¹ The MOQC-PCOM pilot used a primary care pharmacist to conduct comprehensive medication reviews (CMRs) via phone visits for patients with cancer who were receiving active systemic cancer treatment and had at least one of the following pre-existing chronic conditions: diabetes, hypertension, heart failure, depression, and anxiety. Results of the CMR and management recommendations were communicated to the patient’s primary care physician (PCP) and oncologist and/or oncology pharmacist. Although the CMR was the responsibility of the primary care pharmacist in this model, the oncology pharmacist was heavily involved when the primary care pharmacist identified any medication issues related to the patient’s cancer care or when the primary care pharmacist had questions related to the plan for the patient’s cancer treatment. The goals of MOQC-PCOM were to improve management of the chronic disease state, decrease unplanned healthcare utilization, decrease drug-drug interactions, and decrease cancer therapy toxicity.

A total of 96 patients met our inclusion criteria of having a PCP at one Michigan Medicine General Medicine clinic, having an oncologist at the Michigan Medicine Rogel Cancer Center, receiving active cancer treatment, and having at least one of the chronic conditions listed above. Of those 96, a total of 55 had completed CMRs conducted by the primary care pharmacist. The median age was 66 years (range 32–87), 59% were female, 27% were Black, and 67% were White. The median number of medications the patients took was 11 (range 2–23). The following were incidences of comorbid conditions: hypertension, 73%; diabetes, 26%; congestive heart failure, 13%; and psychiatric illness, 42%.

Results from the CMRs included the findings that 77% of patients had changes made to their medication list, 18% were referred to a primary care pharmacist for ongoing chronic disease state management, 22% were referred to a physician for needed follow-up, and 22 medication-related problems (MRPs) were identified.¹² In addition, there were 66 instances of patient education provided related to a medication, disease, or lifestyle. Of the MRPs identified, 32% were related to adherence, 23% to safety, 14% to an indication, and 9% to treatment effectiveness; the remaining 23% were in the “other” category.

The results of this pilot highlight the opportunity that pharmacists have to improve the coordination of care and enhance clinical outcomes for patients with cancer and comorbid conditions. Future work following this pilot will include expansion across the state of Michigan with involvement of other sites, modification to real-time (rather than retrospective) referral, and ultimately the development of a risk model to identify those patients most likely to benefit from the pharmacist’s CMR.

Acknowledgment
The authors wish to recognize and thank the following co-investigators for the MOQC-PCOM pilot: Michelle Azar, PharmD candidate; Karen Farris, PhD; and Emily Joehengen, PharmD.

References

1. Savage P, Mahmoud S. Development and economic trends in cancer therapeutic drugs: a 5-year update 2010-2014. Br J Cancer. 2015;112:1037-1041.
2. Sarfati D, Koczwara B, Jackson C. The impact of comorbidity on cancer and its treatment. CA Cancer J Clin. 2016;66:337-350.
3. Lee SJC, Clark MA, Cox JV, Needles BM, Seigel C, Balasubramanian BA. Achieving coordinated care for complex cancer patients: a multi-team system approach. J Oncol Pract. 2016;12:1029-1038.
4. Cuthbert CA, Hemmelgarn BR, Xu Y, Cheung Y. The effect of comorbidities on outcomes in colorectal cancer survivors: a population-based cohort study. J Cancer Surviv. 2018;12:733-743.
5. Yancik R, Wesley MN, Ries LA, et al. Effects of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA. 2001;285:885-892.
6. Rotenstein LS, Zhang Y, Jacobson JO. Chronic comorbidity among patients with cancer: an impetus for oncology and primary care collaboration. JAMA Oncol. doi:10.1001/jamaoncol.2019.1601 [published online ahead of print July 3, 2019]
7. Dossett LA, Hudson JN, Morris AM, et al. The primary care provider (PCP)-cancer specialist relationship: a systematic review and mixed-methods meta-synthesis. CA Cancer J Clin. 2017;67:156-169.
8. Riechelmann RP, Tannock IF, Wang L, Saad ED, Taback NA, Krzyzanowska MK. Potential drug interaction and duplicate prescriptions among cancer patients. J Natl Cancer Inst. 2007;99:592-600.
9. Riechelmann RP, Zimmermann C, Chin SN, et al. Potential drug interactions in cancer patients receiving supportive care exclusively. J Pain Symptom Manage. 2008;35:535-543.
10. Miranda V, Fede A, Nobuo M, et al. Adverse drug reactions and drug interactions as causes of hospital admission in oncology. J Pain Symptom Manage. 2011;42:342-353.
11. Primary care oncology model overview. Michigan Oncology Quality Consortium website. https://moqc.org/initiatives/pcom/
12. Pharmacy Quality Alliance. PQA Medication Therapy Problem Categories Framework. August 2017. https://www.pqaalliance.org/assets/Measures/PQA%20MTP%20Categories%20Framework.pdf

Staying Current: Advice for New Practitioners

Arpita S. Gandhi, PharmD BCOP
Hematology/Oncology Clinical Pharmacy Specialist
Emory Healthcare
Atlanta, GA

I still remember starting my very first job after the completion of my hematology/oncology pharmacy residency and feeling like I was on top of the world. I had subscribed to a gazillion journals and website updates, and I was all set to be the living encyclopedia of oncology therapeutics for my team—or so I thought. As the years passed by, the burden of staying up-to-date with oncology practice began to weigh heavily on my shoulders, particularly as I started delving into various roles and activities for professional development all while maintaining high standards for patient care activities. Becoming a mother was a game changer. I had to set boundaries for maintaining a healthy work-life balance, which involved coming up with an effective and efficient system that allowed me to stay current with updates in oncology therapeutics.

New information is coming out at an explosive rate.^1,2 In the 1950s, the amount of medical knowledge was expected to double every 50 years. In 2020, medical knowledge is expected to double every 73 days.³ At some point in our professional career, each of us has been told that medicine is a lifelong learning journey; however, we must face the reality that comes with this daunting task. It is incredibly challenging to stay up-to-date with one oncology subspecialty, let alone all subspecialties, internal medicine, infectious diseases, and so on. Staying up-to-date involves two tasks: remembering previously acquired information and learning new information. This article offers some tips that can be used to help you stay current with updates in oncology therapeutics.

Tip 1: Remain curious and always challenge yourself.

During pharmacy school or postdoctorate training, remaining curious and challenging yourself is easy just by virtue of being in a training environment. However, this situation can change after training is completed because of the pressure of daily tasks. It is easier to stick to what we know or are familiar with, and given the pace at which oncology therapeutics is transforming, learned information can become outdated fairly quickly. It is important to work in a challenging environment. Curiosity, even about the tasks that have become second nature, is also important. It is an indispensable attribute and is pivotal for sound clinical reasoning.^4,5 Self-reflection, critical thinking, and teamwork become hollow in the absence of curiosity. Challenge yourself to work as a team with colleagues who may practice differently, and establish a nonthreatening environment that will encourage you and everyone around you to be curious and ask questions (e.g., Why is one regimen picked over another?).

Tip 2: Let others curate resources for you.

Researching primary literature to answer questions encountered on a daily basis will keep you up-to-date, but this will not help you proactively identify issues. The amount of information available at our fingertips is overwhelming. It is up to us to create filters. Subscribe to resources that narrow down the many articles published daily to a dozen or so that may be relevant. Subscribing to a Really Simple Syndication (RSS) feed is an easy and efficient way to stay informed about newly published content. Websites create RSS feeds of their content as a strategy to provide continuous updates to subscribers. Subscribing to RSS feeds is a simple process; it requires an RSS feed address and a program that can translate and show content taken from that feed address. There are many different RSS programs that can display and update information from RSS feeds.⁶

• Table of contents (TOC) alerts: Set up an alert for your favorite journal(s) so that you will receive an email or an updated RSS feed when a new issue is published. This can be set up for an individual journal from the journal’s website or via search engine websites such as PubMed’s MyNCBI feature.^6,7
• Feedly is a tool that pulls information from all over the Web (e.g., blogs, journals, YouTube videos, Twitter feeds) via RSS feeds. Instead of having to visit webpages every few days to find updates, it delivers the same information to one place. The number of unread articles shows up in the easy-to-read feeds on the main page, allowing you to review everything on one dashboard. Notes can be made in these articles, though this feature requires a fee. You can also save articles to personalized boards. Feedly allows you to integrate with numerous applications and easily share content to social media outlets.
• EvidenceAlerts is an integrated e-mail alerting system for healthcare providers (covering key trials from more than 120 journals) at no charge. All citations are prereviewed by research staff to ensure quality and are subsequently rated by physicians for clinical relevance and interest.
• Read by QxMD, a mobile app, is a digital one-stop shop for medical literature. It allows you to get feeds of the medical journals of your choosing and organize and review your personal collection of articles. A unique feature of this app is that it links with your institution’s library account, so you can access full-text articles that your library subscribes to with a single click. You can also make a comment on a paper, save it, share it on social media, or send it to someone.
• Podcasts are an easy way of staying informed if you lack the time to read journals. Several medical journals, including the Journal of Clinical Oncology and Lancet Oncology, and professional organizations publish podcasts (including the recently launched HOPA Now) to summarize or supplement what is published in journals or is being discussed among healthcare providers.

In addition to journals, numerous other websites (e.g., Medscape, Cancer Network, Clinical Care Options, U.S. Food and Drug Administration, and Journal of National Comprehensive Cancer Network 360) provide e-mail subscription services through which the latest medical news, clinical trial coverage, drug updates, journal articles, continuing education activities, and more are delivered.

Tip 3: Use social media.

Social media (Facebook, Twitter, etc.) are not for everyone, and let’s face it—they are not PubMed. However, I personally find it helpful to read what experts and nonexperts alike are talking about, particularly for primary literature. It is important to appreciate opposing perspectives: they may further challenge your viewpoints and cause you to dig deeper. Follow journals or medical/pharmacy organizations on social media to read about the latest updates.

Tip 4: Attend conferences.

Megaconferences such as the American Society of Clinical Oncology or Hematology/Oncology Pharmacy Association annual meetings have attendance numbering in the thousands and are great for accessing a breadth of information and learning about the latest breakthroughs. However, smaller-scale conferences hosted on a local or state level can provide just as much value. Choose conferences that are most relevant to your practice, and try to commit to attending at least one annually.

Tip 5: Use a clinical decision support system.

Clinical decision support systems (e.g., UpToDate) are quickly becoming essential tools for healthcare providers because they provide the most up-to-date evidence-based information (e.g., overview of disease, treatment guidelines) at the point of care. These systems can perform many functions, including, but not limited to, streamlining treatment algorithms based on cancer type.

Tip 6: Teach.

Teaching comes in all shapes and sizes. As pharmacists, we are constantly teaching, whether formally or informally, consciously or subconsciously. We can teach only what we know, so encouraging yourself and all those around you to ask questions is a great way to stay up-to-date. I have found that my best learning comes from teaching. This may be in the form of writing an article, lecturing at a college of pharmacy or at a conference, reviewing mechanisms of action of drugs with a learner, and so much more. We should all consider ourselves both teachers and learners.

Tip 7: Attain board certification.

The Board Certified Oncology Pharmacist program validates that the pharmacist has the advanced knowledge and experience necessary to optimize outcomes for patients with malignant diseases. Attaining board certification and subsequently maintaining it require completion of continuing education and offer you a great way to stay up-to-date.⁸

Tip 8: Interact with peers.

One of the most common and effective ways healthcare providers receive medical updates is from their colleagues. Routine peer-to-peer interaction can be a useful way to stay abreast of changing guidelines and cutting-edge research. Ask fellow pharmacists or providers for their thoughts on a new study or recently updated guidelines, for example.

Tip 9: Engage with pharmacy organizations.

Getting involved in pharmacy organizations, whether at a local, state, or national level, is a great way to stay up-to-date. These organizations offer numerous ways to get involved, ranging from participating on a committee to connecting or collaborating with fellow colleagues. Many organizations also have listservs, which generally involve discussions about issues in clinical practice; pharmacists can submit questions and request feedback from members from various institutions. These are great channels for discussing prominent issues, sharing ideas, and networking with colleagues from across the country.

Although I hope you find some of the tips mentioned in this article useful to you in your efforts to stay current, the most important strategy is to make learning a routine activity rather than limiting it to once or twice a year. I subscribe to numerous TOC alerts, but I graze through most of them to find the most important publications. I carefully choose and pay attention to landmark studies that have led to new drug approvals or have changed treatment strategies. I encourage you to carve out a specific time each day (a few minutes) or week (1–2 hours). The hard part is to not lose motivation and to stay disciplined about finding time. There are many ways to learn, and no single way is ideal for everyone. Regardless of your learning style, embrace the concept of lifelong learning—I assure you that it will make you a better pharmacist!⁹

Being an oncology pharmacist is a great privilege. Staying current may seem like a daunting task, but if you make curiosity the foundation of patient care, the task is doable. We make a commitment to serve our patients when we take the pharmacist’s oath. We owe it to ourselves and our profession to maintain this commitment.

References

1. Warner JL. Grappling with the data explosion in oncology. Oncol Hematol Rev. 2015;11: 1023.
2. Beatty PA. Coping with abundance: the burden of progress in medical oncology. Oncologist. 2012;17:294-295.
3. Poorman E. Staying current in medicine: advice for new doctors. NEJM Knowledge+ website. https://knowledgeplus.nejm.org/blog/staying-current-in-medicine-advice-for-new-doctors/. Published November 10, 2016.
4. Adashi EY, Ahmed AKH, Gruppuso PA. The importance of being curious. Am J Med. 2019;132:673-674.
5. Dyche L, Epstein RM. Curiosity and medical education. Med Educ. 2011;45:663-668.
6. Dubuque EM. Automating academic literature searches with RSS feeds and Google Reader. Behav Anal Pract. 2011;4:63-69.
7. Fox BI, Felkey BG. Keeping up with advancements in health information technology. Hosp Pharm. 2016;51:345-346.
8. Oncology pharmacy. Board of Pharmacy Specialties website. 2019. https://www.bpsweb.org/bps-specialties/oncology-pharmacy/#1517761118361-6c02bae3-f5a0151778001577715178540776891517858333825.
9. Mandrola J. A mid-career perspective on lifelong learning in medicine. NEJM Knowledge+ website. https://knowledgeplus.nejm.org/blog/a-mid-career-perspective-on-lifelong-learning-in-medicine/. Published March 12, 2015.

Benign Hematology for the Oncology Pharmacist

Alexis Kuhn, PharmD BCOP
Pediatric Oncology Pharmacist—Ambulatory Services
Mayo Clinic
Rochester, MN

Most people think of hematology as malignant hematology. This penchant for malignant hematology is reflected in the oncology pharmacy residency standards and the Board Certified Oncology Pharmacist (BCOP) content outline.^1,2 Despite this, hematology/oncology pharmacists are often called upon to care for benign hematology patients in clinical practice. The goal of this review is to familiarize hematology/oncology pharmacists with fundamental benign hematology concepts that can be employed during care for this population.

Meet the Players

Erythrocytes
“Normal” adult hemoglobin (HbA) consists of two α- and two β-globin subunits (α₂β₂). Fetal hemoglobin (HbF) consists of two α- and two γ-globin subunits (α₂γ₂) and has greater oxygen-binding affinity than HbA. HbF production nadirs in the postnatal period.³

Leukocytes
Hematopoietic progenitors differentiate into either myeloid lineage (neutrophils and other granulocytes) or lymphoid lineage (T and B cells). Both elements are crucial for immune function.⁴

Platelets
Platelets are vital for hemostasis. GPIbα on the platelet surface binds to endothelial-bound von Willebrand factor (vWF) to initiate platelet adhesion.^5,6

Meet the Disorders

Hemostatic disorders
Von Willebrand disease (VWD) is the most common inherited bleeding disorder. In addition to its role in platelet adhesion, vWF also stabilizes circulating factor VIII (FVIII). Types 1 and 3 VWD are quantitative disorders of vWF, and Type 2 is a qualitative disorder.^6,7 Hemophilia is an X-linked disorder that arises from absent or diminished production of FVIII (hemophilia A) or factor IX (FIX; hemophilia B). Hemophilia severity is defined by baseline factor activity level: severe (<1%), moderate (1%–5%), or mild (5%–40%).8 Severe disease is characterized by spontaneous and potentially life-threatening bleeds. Neutralizing antibodies produced in response to exogenous factors, known as inhibitors, afflict ~30% of patients with severe hemophilia A and ~3%–5% of patients with hemophilia B.⁹

Hemoglobinopathies
Thalassemias are quantitative disorders of hemoglobin, resulting from diminished production of either α- or β-globin. They can be categorized by affected gene, major/intermedia/minor designation, and transfusion-dependent/independent status. Transfusions often begin at a young age, making potentially fatal siderosis a lifelong concern.¹⁰

Sickle cell disease arises from a point mutation in the β-globin gene. Mutant hemoglobin (HbS, α₂βS₂) polymerizes when deoxygenated, which results in the characteristic sickled shape of affected erythrocytes.11 Clinical sequelae include pain crises, acute chest syndrome, and stroke. In general, patients with HbSS and HbSβ⁰ thalassemia tend to have more severe clinical phenotypes than patients with other heterozygous genotypes (i.e., HbSC, HbSβ⁺ thalassemia).¹¹

Cytopenias
Cytopenias result from either inherent marrow failure or immune destruction. Bone marrow failure syndromes can be inherited or acquired, and they result in either single- (e.g., severe congenital neutropenia) or multi-lineage loss (e.g., aplastic anemia).¹² Common immune cytopenias include immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome (typically coincident ITP + AIHA). Characterization of the causative antibody is particularly useful in AIHA, where thermoreactivity directs treatment approach.^13,14

Meet the Drugs

Treatment of hemostatic disorders
Possible treatment options for VWD include desmopressin and vWF concentrates. Desmopressin increases vWF and FVIII, also making it useful for treating mild or moderate hemophilia A.⁷

The treatment of choice for severe hemophilia has traditionally been prophylaxis with clotting factor concentrates.⁸ Major differentiating features between concentrates include factor (FVIII, FIX, vWF, etc.), source (plasma-derived vs. recombinant), and presence of modifications. Concerns of viral transmission have plagued the plasma-derived concentrates, but modern manufacturing practices minimize the risk of transmission.¹⁵ Recombinant factors carry no risk for viral transmission, but conflicting reports suggest that certain recombinant factors may have a higher risk of inhibitor development than plasma-derived factors containing vWF.¹⁶ Extended half-life (EHL) factors employ various modifications (e.g., pegylation, albumin fusion) to reduce the frequency of infusion. EHL FIX products have achieved a 4–6 times half-life extension in contrast to the 1.5–2 times extension of the EHL FVIII products.¹⁷

Emicizumab is a monoclonal antibody approved for hemophilia A. By binding FIXa and FX, emicizumab mimics the activity of FVIII, making it a therapeutic option for patients with and without inhibitors as evidenced in the HAVEN trials.^18-21 Unlike the intravenous clotting factor concentrates, emicizumab is a subcutaneous injection that can be given one to four times per month.^21,22 Other therapeutic options for patients with inhibitors include bypassing agents (FEIBA and rFVIIa) and immune tolerance induction.^9,23

Treatment of hemoglobinopathies
Iron chelators are paramount in managing chronic transfusion therapy associated with hemoglobinopathies. Deferoxamine is given as daily subcutaneous infusions, or, less commonly, as intermittent high-dose intravenous infusions.²⁴ Deferasirox and deferiprone are enteral options, but deferiprone carries a risk for agranulocytosis. Combination chelation can be deployed for refractory cases.^25,26

Therapeutic options for sickle cell disease have expanded in recent years. Hydroxyurea has been used for several decades; it induces HbF production and reduces the frequency of pain crises, acute chest syndrome, and transfusions.^27,28 The first approved novel agent, L-glutamine, works by maintaining reduction and oxidation balance. L-glutamine was shown to reduce pain crises compared to placebo (three vs. four episodes per year, p = .005) in a phase 3 trial.²⁹ Crizanlizumab is an intravenous P-selectin inhibitor that interrupts adhesion of cells to the vascular endothelium. In the SUSTAIN trial, high-dose crizanlizumab was shown to reduce pain crises compared to placebo (1.6 vs. 3 episodes per year, p = .01).³⁰ Voxelotor is an oral agent that inhibits HbS polymerization. In the HOPE trial, voxelotor increased hemoglobin >1 g/dL from baseline in 51% participants.³¹ Studies of voxelotor, crizanlizumab, and L-glutamine included patients with and without concomitant hydroxyurea; however, there is currently no standard for how to sequence these agents in clinical practice.³²

Treatment of cytopenias
Inappropriate immune system activity can be dampened by various approaches: corticosteroids, intravenous immunoglobin, rituximab, and other immunosuppressants.^13,14 Warm AIHA is typically more responsive to immunosuppressants than cold AIHA.¹⁴ Immunosuppression with equine antithymocyte globulin plus cyclosporine, with or without eltrombopag, is the standard of care for transplant-ineligible patients with severe aplastic anemia.^33,34 Eltrombopag is a thrombopoietin (TPO) receptor agonist thought to have hematopoietic stem cell-stimulatory effects and is approved by the U.S. Food and Drug Administration for refractory aplastic anemia; larger trials are under way to confirm early positive results in front-line therapy.^34,35 In addition to its activity in aplastic anemia, eltrombopag is used to treat chronic ITP, as is the parenteral TPO agonist, romiplostim.³⁶ Caplacizumab is an anti-vWF antibody with activity in acquired thrombotic thrombocytopenia purpura. ^37,38

References

1. Required competency areas, goals, and objectives for postgraduate year two (PGY2) oncology pharmacy residencies. American Society of Health-System Pharmacists website. https://www.ashp.org/-/media/assets/professional-development/residencies/docs/pgy2-newly-approved-oncology-pharmacy-2016.ashx. Accessed May 13, 2020.
2. Board of Pharmacy Specialties. Board of Pharmacy Specialties Oncology Pharmacy Specialist Certification Content Outline/Classification System. https://www.bpsweb.org/wp-content/uploads/OncContentOutline2017.pdf. Accessed May 13, 2020.
3. Schechter AN. Hemoglobin research and the origins of molecular medicine. Blood. 2008;112:3927-3938.
4. Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood. 1993;81:2844-2853.
5. Holinstat M. Normal platelet function. Cancer Metastasis Rev. 2017;36:195-198.
6. Peyvandi F, Garagiola I, Baronciani L. Role of von Willebrand factor in the haemostasis. Blood Transfus. 2011;9(Suppl 2):s3-s8.
7. Leebeek FW, Eikenboom JC. Von Willebrand’s disease. N Eng J Med. 2016;375:2067-2080.
8. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19:e1-47.
9. Carcao M, Goudemand J. Inhibitors in Hemophilia: A Primer. 5th ed. Montreal, Canada: World Federation of Hemophilia; 2018.
10. Viprakasit V, Ekwattanakit S. Clinical classification, screening and diagnosis for thalassemia. Hematol Oncol Clin North Am. 2018;32:193-211.
11. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. 2017;376:1561-1573.
12. Sieff CA. Introduction to acquired and inherited bone marrow failure. Hematol Oncol Clin North Am. 2018;32:569-580.
13. Kim TO, Despotovic JM. Primary and secondary immune cytopenias: evaluation and treatment approach in children. Hematol Oncol Clin North Am. 2019;33:489-506.
14. Go RS, Winters JL, Kay NE. How I treat autoimmune hemolytic anemia. Blood. 2017;129:2971-2979.
15. Farrugia A. Guide for the Assessment of Clotting Factor Concentrates. 3rd ed. Montreal, Canada: World Federation of Hemophilia; 2017.
16. Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of Factor VIII and neutralizing antibodies in hemophilia A. N Eng J Med. 2016;374:2054-2064.
17. Graf L. Extended half-life factor VIII and factor IX preparations. Transfus Med Hemother. 2018;45:86-91.
18. Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017;377:809-818.
19. Young G, Liesner R, Chang T, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019;134:2127-2138.
20. Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med. 2018;379:811-822.
21. Pipe SW, Shima M, Lehle M, et al. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol. 2019;6:e295-e305.
22. Shima M, Nogami K, Nagami S, et al. A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia. 2019;25:979-987.
23. Carcao M, Escuriola-Ettingshausen C, Santagostino E, et al. The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab. Haemophilia. 2019;25:676-684.
24. Kalpatthi R, Peters B, Kane I, et al. Safety and efficacy of high dose intravenous desferrioxamine for reduction of iron overload in sickle cell disease.Pediatr Blood Cancer. 2010;55:1338-1342.
25. Kontoghiorghe CN, Kontoghiorghes GJ. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent. Drug Des Devel Ther. 2016;10:465-481.
26. Gomber S, Jain P, Sharma S, Narang M. Comparative efficacy and safety of oral iron chelators and their novel combination in children with thalassemia. Indian Pediatr. 2016;53:207-210.
27. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. N Engl J Med. 1995;332:1317-1322.
28. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011;377:1663-1672.
29. Niihara Y, Miller ST, Kanter J, et al. A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med. 2018;379:226-235.
30. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376:429-439.
31. Vichinsky E, Hoppe CC, Ataga KI, et al. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381:509-519.
32. Bradt P, Spackman E, Synnott PG, et al. Crizanlizumab, Voxelotor, and L-Glutamine for Sickle Cell Disease: Effectiveness and Value. Boston, MA: Institute for Clinical and Economic Review; 2020. Available at https://icer-review.org/wp-content/uploads/2019/08/ICER_SCD_Evidence-Report_031220.pdf
33. Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Eng J Med. 2011;365:430-438.
34. Scheinberg P. Activity of eltrombopag in severe aplastic anemia. Blood Adv. 2018;2:3054-3062.
35. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Eng J Med. 2017;376:1540-1550
36. Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3:3829-3866.
37. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab for acquired thrombotic thrombocytopenia purpura. N Eng J Med. 2016;374:511-522.
38. Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenia purpura. N Eng J Med. 2019;380:335-346.

Barriers to the Initiation of Oral Oncolytics

Chelsea Gustafson, PharmD BCOP
Oncology Pharmacy Specialist
Community Health Network: Community Regional
Cancer Centers
Kokomo, IN

Caroline Quinn, PharmD BCOP
Clinical Pharmacy Specialist
The University of Texas MD Anderson Cancer Center
Houston, TX

Oral anticancer therapies are an increasingly prevalent part of cancer treatment. Oral cytotoxic agents, small-molecule inhibitors, and other medications may offer several advantages over parenteral anticancer options. These advantages include the convenience of completing therapy at home and a possible decrease in the frequency of office visits. In addition, some patients may appreciate the enhanced sense of responsibility that stems from administering their therapy at home.¹ 

Despite the increasing use of oral anticancer therapy, the process for accessing these medications is often complex and can be time-consuming and confusing for patients and healthcare providers alike. Patients, providers, and other staff members may have to contact an extensive list of organizations, including insurance companies, specialty pharmacies, drug manufacturers, and patient assistance foundations before the patient is ultimately able to access the prescribed medication. Although the particulars of drug procurement, drug cost, and insurance coverage vary from patient to patient, several common barriers to medication access arise, and pharmacists should be aware of these when helping patients who are initiating oral anticancer therapies. In this article, we discuss some of those barriers by using the experience of one patient, PT, as  an example.

PT was a 66-year-old female with metastatic estrogen receptor/progesterone receptor-positive, human epidermal growth factor receptor 2–negative breast cancer diagnosed in late 2019. Her oncologist determined that a CDK4/6 inhibitor and anastrozole were the treatment of choice. A prescription for a CDK4/6 inhibitor was sent to the health network’s specialty pharmacy. PT had Medicare Part D insurance, which required a prior authorization for the new medication. The prior authorization was submitted by a medication assistance coordinator (MAC), a pharmacy technician working specifically to help patients access oncology medications. PT’s health system was very fortunate to have MACs;  many health systems do not have such assistance. Fortunately, PT’s prior authorization was approved on the same day the prescription was sent. However, the copayment for the CDK4/6 inhibitor was more than $2,000 per month, an unaffordable amount by almost any standard. PT’s team also learned that the network specialty pharmacy was not contracted to dispense this specific medication. Therefore, the prescription was sent to another specialty pharmacy. Luckily, the medication’s manufacturer offered a voucher program for the first cycle of the drug. The MAC assigned to PT’s case registered her for the voucher program and provided the patient and voucher information to the new specialty pharmacy. A few days later, the first cycle of the drug was sent to PT with no out-of-pocket cost.

Unfortunately, PT was unable to pay $2,000 monthly for subsequent cycles. PT’s MAC filled out an application for foundational support to help cover future copayments. After extensive income information was obtained from PT (including sensitive information like her tax statements from the previous year and Social Security number), the application was filled out, PT’s oncologist signed the application, and the MAC faxed the packet of information to the foundation. Five days later, PT’s team heard that the foundation was accepting only re-enrollments and that no new patients would be accepted. PT’s team then repeated this application process with the drug manufacturer’s patient assistance program. Approximately 2 weeks later, PT’s team received word that she had been approved to receive the CDK4/6 inhibitor through the patient assistance program until the end of 2020. PT then finally received her second cycle of the drug in the mail, 2 days after she was scheduled to start cycle 2.

PT and her healthcare team ran into some of the most common barriers in oral anticancer therapy access (Figure 1-see PDF). First, as happens with many newly prescribed oral anticancer therapies, PT’s insurance company required a prior authorization for the specialty medication. Although the healthcare team did not have to do this in PT’s case, an appeal letter, peer-to-peer communication, or both are often required in addition to the initial prior authorization request. If that appeal is denied (typically after a minimum of a 72-hour turnaround time), then an external appeal can sometimes be pursued, with another 72-hour turnaround time. The denial of the external appeal, if it occurs, is often the end of the road for prescription insurance coverage. These processes are time-consuming for healthcare teams and may delay a patient’s ability to begin therapy, especially for health systems that lack personnel trained for and designated to the task of coordinating medication assistance.

As seen with PT’s copayment, patients may face significant cost sharing when they are prescribed oral anticancer therapies. The case is different with chemotherapy by infusion: drugs given in the infusion center are covered by medical insurance, not the prescription plan. This difference may cause confusion for patients and members of the healthcare team.  Providers are often unaware of drug coverage at the point of prescribing and are therefore unable to consider affordability in treatment planning. If a patient is ultimately unable to afford the prescribed medication, the process of repeating treatment planning and prescribing an alternative therapy creates even more delays in treatment.1 Changing therapy may cause stress for patients who believe that the initially prescribed medication was the best choice for them. Significant delays in therapy resulting from insurance barriers can also lead to psychological harm for patients who believe that their cancer is progressing between treatments.

Patients with commercial insurance may be eligible for a copay card to cover a portion of the out-of-pocket cost of their medication, if the manufacturer offers a copay card. However, a large proportion of patients at many cancer centers are 65 years of age or older and have Medicare Part D insurance. These patients, as well as patients with Medicaid, are not eligible for copay cards. Patients with either Medicare/Medicaid or commercial insurance may be eligible for patient assistance programs through manufacturers and foundations. These programs often have specific requirements set by the organization offering the funding. Each program requires a separate application, and some of them have income requirements that may eliminate middle-class or higher-earning patients who still find copayments like PT’s challenging to afford. The turnaround time for approval or denial of these programs also varies and may contribute to a delay in starting therapy. Most assistance programs are reserved for products that are still branded, as many oral anticancer therapies are. However, for the few generic options, finding patient assistance can be particularly challenging. For treatments such as capecitabine, healthcare teams may turn to avenues like online coupons to decrease cost, but patients may still be left with a shockingly high copay. Furthermore, at the first of the year many patients must meet a deductible. Usually manufacturer copay cards cover a percentage of the total cost, and the deductible tends to be higher for more expensive therapies.

As PT’s story demonstrates, the path to oral anticancer therapy access is often convoluted and time-consuming. Because patients frequently need new prescriptions when dose adjustments are made to the therapies or when insurance coverage changes, the procurement process may need to be repeated during therapy. Many patients are unaware of potential barriers or ways to overcome them, and they may be frustrated and confused when these barriers lead to delays in therapy. In this process, the pharmacy team is often viewed as holding the magic key to drug acquisition. Although unfortunately we can’t work magic, pharmacists do play a vital role in drug procurement, education of patients and healthcare providers about the process, and coordination of the many people involved in successfully prescribing and dispensing oral anticancer therapies. As oral therapies become more common in the treatment of cancer, awareness of the long and winding road of access to these therapies must be at the forefront of the oncology pharmacist’s practice. 

Reference

1. Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: Oral chemotherapy. J Natl Compr Canc Netw. 2008;6 Suppl 3: S1-S14.

Deprescribing Interventions for Older Adults with Cancer and Polypharmacy

Andrew Whitman, PharmD BCOP
Lead Clinical Pharmacist—Oncology/Palliative Care
University of Virginia Health System
Charlottesville, VA

Polypharmacy has been called “America’s other drug problem.”1 Overuse of medications, especially in older adults, is a multifaceted issue and a large burden to our healthcare system. A diagnosis of cancer adds an additional layer of complexity.¹ A common barrier to evaluating polypharmacy is the heterogeneity of definitions and processes in the current medical literature. The study reviewed here, “Pharmacist-Led Medication Assessment and Deprescribing Intervention for Older Adults with Cancer and Polypharmacy: A Pilot Study,” attempted to standardize polypharmacy assessment and subsequent deprescribing interventions in older adults with cancer.²

In this study, adult patients age 65 years or older with a diagnosis of cancer (of any type) were assessed in the Geriatric Oncology Clinic at the University of Virginia Health System.² Each patient was evaluated by a nurse, physical therapist, pharmacist, and geriatric oncologist. The pharmacist’s role on this team was to complete a polypharmacy assessment and add it to the overall comprehensive geriatric assessment (CGA) score. A CGA helps determine existing, treatable health problems in older adults and aims to improve overall care outcomes (a detailed review of the CGA is beyond the scope of this review³). The first step to any effective deprescribing intervention is creating an accurate medication list. Therefore, the majority of the time was spent consolidating medication information. This included review of electronic health records, outside pharmacy records, patient reports, and caregiver feedback. All types of medications and supplements were included in the polypharmacy review. A deprescribing process was then applied to each inappropriate therapy.

The following themes were core to the success of the deprescribing interventions in this study:

Medication-condition matching

As displayed in (Figure 1-see PDF) in the study, the medication-condition matching chart helped organize and highlight the specific indications for each therapy. Medications without obvious indications were flagged for further investigation and deemed potential deprescribing candidates. The chart also included “potential problems” in the medication-condition matching chart in order to help identify prescribing cascades or new medication-related adverse effects.

Why is this important?
This visual representation of medications brings to light the extent of medication burden and is often shocking to patients and providers. A missing indication can help prompt the question of whether prescribing cascades or prescribing inertia has occurred.

Comprehensive potentially inappropriate medication review (utilizing three assessment tools)

In this study, a three-tool assessment was used in order to be as comprehensive as possible. The Beers Criteria, Screening Tool of Older Persons’ Prescriptions, and Medication Appropriateness Index have the strongest data supporting use in older adults with cancer.

Why is this important?
The concurrent, sequential use of these tools was chosen to maximize PIM identification; this combination of implicit and explicit screening tools proved to be effective. This is a novel method of polypharmacy evaluation that had not been evaluated in other studies in older adults with cancer.

Determination of medication-related “goals”

In this study, medication-related goals were assessed. This entailed verbal discussions regarding patient and caregiver opinions and attitudes toward general medication use (e.g., minimizing pill burden, optimizing quality of life, focusing on chronic disease state management). The study recognized that a limitation to evaluating medication-related goals was the lack of a well-validated patient-reported goals metric.

Why is this important?
In the course of pursuing deprescribing interventions, it is essential to be person-centric in making decisions. Patients with existing attitudes and opinions about deprescribing can make the action of deprescribing easier and more efficient. Methods to assess patient-reported outcomes related to medication “goals” warrants additional exploration in future studies.

Discussion of barriers to deprescribing

Patient and caregiver barriers to deprescribing were informally evaluated during each direct patient encounter. Each patient appointment was on average 15 minutes, and the majority of time was spent directly discussing patient and caregiving questions and fears about deprescribing. Barriers to deprescribing for providers were not assessed in this study.

Why is this important?
A growing body of literature is evaluating patient and provider barriers to deprescribing. It is important to identify barriers to deprescribing as soon as possible—this helps to drive decision making and improves transparency between providers. Since the completion of this pilot, studies looking at a method of assessing barriers to deprescribing has been validated (i.e., the Patients’ Attitudes Towards Deprescribing questionnaire).^4-6 Common barriers for providers include reluctance to stop medications initiated by other providers, lack of ownership of the deprescribing process, and underappreciation of the scale of polypharmacy-related harm. Common barriers for patients include the belief that taking a medicine to prevent or treat a disease is always needed (“pill for every ill”), fear of drug withdrawal, and feeling “abandoned” or not worthy of treatment.

In our study,² data were collected for 26 patients during an 8-month period. The 26 patients in this study were taking a total of 312 medications, of which 197 were prescription and 113 were over-the-counter or alternative therapies. The mean number of medications per patient was 12. The Beers Criteria alone identified 38 potentially inappropriate medications (PIMs) compared to 119 PIMs with the three-tool assessment; a mean of 5 PIMs per patient was identified. After the application of the three-tool assessment, 73% of PIMs identified were deprescribed in real time by the pharmacist and geriatric oncologist, resulting in a mean of three medications deprescribed per patient. Based on University Health System Consortium outcomes cost data, healthcare expenditures of $111,390 were potentially avoided as a result of PIM assessment and deprescribing. Fifty-two percent of patients reported no barriers related to stopping medications and felt comfortable with the process. Of the patient-reported barriers to deprescribing, the most common concern was fear of return of symptoms or worsening of the underlying condition being treated.

This is one of the first studies to demonstrate the effectiveness of a standard approach to polypharmacy assessment and deprescribing in older adults with cancer. The three-tool assessment process should be incorporated into interdisciplinary assessments of older patients with cancer and validated in future studies. Deprescribing should be seen as an individualized assessment of medications that is driven by patient and caregiver goals as well as evidence-based medicine.

References

1. Guharoy R. Polypharmacy: America’s other drug problem. Am J Health Syst Pharm. 2017;74:1305-1306.
2. Whitman AM, DeGregory KA, Morris AL, et al. Pharmacist-led medication assessment and deprescribing intervention for older adults with cancer and polypharmacy: a pilot study. Support Care Cancer. 2018;26:4105-4113.
3. Parker SG, McCue P, Phelps K, et al. What is a comprehensive geriatric assessment (CGA)? An umbrella review. Age Ageing. 2018;47:149-155.
4. Reeve E, Shakib S, Hendrix I, et al. Development and validation of the Patients’ Attitude Towards Deprescribing (PATD) questionnaire. Int J Clin Pharm. 2013;35:51-56.
5. Reeve E, Low LF, Shakib S, Hilmer SN. Development and validation of the revised Patients’ Attitudes Towards Deprescribing (rPATD) questionnaire: versions for older adults and caregivers. Drugs Aging. 2016;33 (12):913-928.
6. Reeve E, Anthony AC, Kouladjian O’Donnell L, et al. Development and pilot testing of the revised Patients’ Attitudes Towards Deprescribing questionnaire for people with cognitive impairment. Australas J Ageing. 2018;37:e150-e154.

Sequencing the Treatment of Metastatic Castration-Resistant Prostate Cancer

Cassandra Hacker, PharmD
PGY-2 Oncology Pharmacy Resident
Barnes-Jewish Hospital
St. Louis, MO

Katie Lentz, PharmD BCOP
PGY-2 Oncology Residency Program Director
Oncology Clinical Pharmacy Specialist
Barnes-Jewish Hospital
St. Louis, MO

Prostate cancer is the second most common cancer among males, with an estimated 191,130 new cases in 2020, and the second leading cause of cancer-related death in males in the United States.^1,2 Localized and regional disease confers a relatively optimistic prognosis, with 5-year overall survival of 100% versus 30% for patients with advanced disease.2 Treatment of advanced prostate cancer is driven by androgen deprivation therapy via surgical or medical castration with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist, with or without an antiandrogen or abiraterone.² The goal is to achieve castrate levels of testosterone <50 ng/dL to reduce hormonal stimulation of cancer growth. Eventually, many patients with metastatic disease develop castration resistance, known as metastatic castration-resistant prostate cancer (mCRPC), characterized by cancer progression despite the use of standard androgen deprivation therapy and maintainence of  castrate levels of testosterone.^2,3

The recommended treatments used in the mCRPC setting include taxanes (docetaxel and cabazitaxel), androgen-signaling-targeted inhibitors (ASTIs) (abiraterone and enzalutamide), sipuleucel-T, and radium-223 dichloride.⁴ Cabazitaxel is a next-generation taxane approved for mCRPC in patients previously treated with a docetaxel-based regimen.⁵ It has been shown to retain activity in patients who previously failed treatment with docetaxel or an ASTI.^5-7 Abiraterone inhibits CYP17A1, an essential enzyme involved in androgen synthesis, which is often upregulated in mCRPC and contributes to resistance.⁸ Enzalutamide inhibits the androgen receptor and is able to overcome upregulated androgen-receptor expression implicated in resistance and disease progression.⁹ Historically, minimal data were available to guide the sequence of therapies for mCRPC. This article summarizes recently published studies evaluating the sequencing of cabazitaxel, abiraterone, and enzalutamide for mCRPC.

Cabazitaxel Versus Abiraterone or Enzalutamide in mCRPC: The CARD Trial

De Wit and colleagues conducted a multicenter randomized open-label trial at 62 sites across Europe, investigating whether cabazitaxel is superior to abiraterone or enzalutamide in mCRPC patients previously treated with docetaxel and an ASTI.¹⁰ Included were mCRPC patients previously treated with at least three cycles of docetaxel with disease progression occurring during 12 months of therapy with abiraterone or enzalutamide before or after the docetaxel. Patients were randomized 1:1 to receive cabazitaxel or an ASTI not previously given, and the treatments continued until imaging-based confirmation of disease progression, unacceptable toxicity, initiation of subsequent therapy, or another request to discontinue. Cabazitaxel was administered as 25 mg/m2 intravenously (IV) over 1 hour every 3 weeks plus prednisone 10 mg orally daily according to the European drug label. Abiraterone was administered as 1000 mg orally daily plus prednisone 5 mg orally twice daily to patients who had previously received enzalutamide. Enzalutamide was given as 160 mg orally daily to patients who had previously received abiraterone. Crossover to the opposite treatment arm was allowed upon disease progression. Patients were stratified according to Eastern Cooperative Oncology Group (ECOG) performance status 0–1 versus 2, time to disease progression ≤6 months versus >6–12 months, and timing of previous ASTI before docetaxel versus after docetaxel. The primary outcome evaluated was imaging-based progression-free survival (PFS).

Between November 2015 and November 2018, 255 subjects were included in this study, with 129 patients randomized to receive cabazitaxel and 126 randomized to receive either abiraterone (n = 58) or enzalutamide (n = 66). The median duration of treatment was longer in the cabazitaxel group (22 weeks vs. 12.5 weeks), and more patients discontinued therapy in the ASTI group overall (63.5% with cabazitaxel vs. 79.9% with an ASTI), mostly because of disease progression (43.7% vs. 71%, respectively). At median follow-up at 9.2 months, median PFS was 8 months versus 3.7 months in favor of cabazitaxel (hazard ratio [HR] = 0.54, p < .001). Median overall survival (OS) was significantly improved with cabazitaxel (13.6 months vs. 11 months; HR = 0.64, p = .008). Prostate-specific antigen (PSA), tumor, and pain response rates were all improved with cabazitaxel (PSA response, 35.7% vs. 13.5%, p < .001; tumor response, 37% vs. 12%, p = .004; pain response, 45% vs. 19.3%).

In a comparison of safety outcomes, the proportion of patients with adverse effects (AEs) of any grade and serious AEs were similar (38.9% vs. 38.7% serious AEs). AEs leading to discontinuation were more common with cabazitaxel (19.8% vs. 8.9%), but cabazitaxel patients required fewer dose reductions (21.4% vs. 37.9%). The most common grade ≥3 AEs reported for cabazitaxel versus ASTI respectively were infection (7.9% vs. 7.3%), musculoskeletal pain (1.6% vs. 5.6%), fatigue (4% vs. 2.4%), diarrhea (3.2% vs. 0), and peripheral neuropathy (3.2% vs. 0).

The CARD trial concluded that mCRPC patients previously treated with docetaxel and an ASTI achieved significantly longer imaging-based PFS and OS with cabazitaxel versus the alternative ASTI, despite crossover between treatment arms. Statistically significant benefit or trend toward benefit with cabazitaxel was seen across all subgroups, including ECOG performance status 0–1 versus 2, timing of ASTI before or after docetaxel, disease severity, and type of previous progression.¹⁰ These results align with previous data revealing poor outcomes for patients immediately initiating an alternative ASTI after progression, likely because of similar resistance mechanisms between agents.¹¹ Regarding therapy sequencing, this trial suggests that cabazitaxel should be used before the alternative ASTI in subsequent treatment of mCRPC.¹⁰ Conclusions from this trial are limited by its open-label design, lack of blinding for central review of imaging, and geographic limitation to Europe using the approved European cabazitaxel dosage. In addition, the CARD study lacks a subgroup analysis evaluating efficacy specific to abiraterone followed by randomization to enzalutamide or cabazitaxel. It is unclear whether cabazitaxel would still be favored if this sequence was specified.

Sequencing of Enzalutamide and Abiraterone in mCRPC

Khalaf and colleagues conducted a randomized open-label trial at six centers in British Columbia, Canada, assessing the ideal sequencing of ASTIs in patients with newly diagnosed mCRPC (N = 202).12 Patients were randomized 1:1 to abiraterone 1000 mg orally daily plus prednisone 5 mg orally twice daily, followed by enzalutamide 160 mg orally daily after PSA progression (abiraterone-enzalutamide, n = 101), or the opposite sequence (enzalutamide-abiraterone, n = 101). Treatment continued until symptomatic or clinical disease progression, unacceptable toxicity, or patient withdrawal. Patients were allowed prior docetaxel treatment for castration-sensitive disease and had to maintain LHRH agonist treatment throughout the study if they had no history of orchiectomy. Patients were excluded if they had previously taken abiraterone, enzalutamide, or another experimental ASTI. Primary outcomes included time to second PSA progression (time from start of first-line treatment to confirmed PSA progression on second-line treatment, or death from prostate cancer before crossover, whichever occurred first) and proportion of patients with PSA response on second-line therapy.

Patients were enrolled from October 2014 to December 2016 and had a median 22.8 months follow-up for analysis of the intention-to-treat population. At data cutoff, 72% and 74% from the abiraterone-enzalutamide group and enzalutamide-abiraterone group, respectively, had crossed over to second-line therapy. For the primary outcomes, median time to second PSA progression was significantly longer in the abiraterone-enzalutamide group (19.3 months vs. 15.2 months; HR = 0.66, p = .036), and PSA response with second-line treatment was significantly higher with abiraterone-enzalutamide (36% vs. 4%; p < .0001). Median time to PSA progression on second-line treatment was also significantly longer with abiraterone-enzalutamide (3.5 months vs. 1.7 months; HR = 0.42, p < .0001). However, no significant difference was seen in median OS (28.8 months vs. 24.7 months; p = .23), nor in median time to first progression (11.2 months vs. 10.2 months; p = .78), although PSA response rate with first-line treatment was significantly higher with enzalutamide-abiraterone (68% vs. 82%; p = .023).

Regarding safety outcomes, serious AEs were more common with enzalutamide-abiraterone (15% vs. 20%), and more patients on enzalutamide required dose reductions (6% vs. 18% with first-line treatment and 19% vs. 5% with second-line treatment).

In summary, enzalutamide showed significantly improved activity as a second-line agent over abiraterone, with prolonged time to second progression and a higher PSA response rate. Each drug was equally effective in the first-line setting according to median time to first PSA progression, despite higher PSA response in the first-line setting with enzalutamide. This study suggests that the greatest clinical benefit comes from the sequencing of agents with abiraterone followed by enzalutamide. Improved time to second PSA progression in the abiraterone-enzalutamide group seems to have been driven by second-line activity of enzalutamide, which was improved compared with abiraterone. A possible mechanism behind the efficacy of enzalutamide in the second-line setting is its ability to overcome abiraterone resistance conferred by progesterone-activated, androgen receptor ligand–binding domain mutations L702H and T878A, found in approximately 15%–20% of mCRPC cases.^13,14

Conclusion

The CARD study suggests that cabazitaxel followed by an ASTI after relapse on docetaxel and the opposite ASTI is useful.¹⁰ Khalaf and colleagues compared sequences of ASTIs in the upfront setting of mCRPC treatment, with results showing improved outcomes using abiraterone followed by enzalutamide.12 Combining the results of these studies, new research questions emerge, such as whether cabazitaxel is more efficacious when used before or after abiraterone, and, similarly, whether abiraterone is more efficacious when used before or after docetaxel.

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