HOPA Publications Committee

Ashley Glode, PharmD BCOP, Chair

Megan Bodge, PharmD BCOP, Vice Chair

Edward Li, PharmD, Board Liaison

Brandi Anders, PharmD BCOP

Morgan Belling, PharmD

Megan Brafford May, PharmD BCOP

Lisa M. Cordes, PharmD BCOP BCACP

Morgan E. Culver, PharmD BCOP

Craig W. Freyer, PharmD BCOP

Marc Geirnaert, BSc Pharm

Carolyn Oxencis, PharmD BCOP BCPS

Christan M. Thomas, PharmD BCOP

Sarah Ussery, PharmD BCOP

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Board Update: The Value Proposition

Sarah Scarpace Peters, PharmD MPH BCOP
HOPA President

What does it mean to provide value in cancer care? This was a central question posed to a record-breaking number of attendees at the 4th Annual HOPA Oncology Pharmacy Practice Management Program (PMP), held September 23–24, 2016, in Chicago, IL. Peter Bach, MD MPP, served as the first-ever keynote speaker for the PMP and kicked off the meeting with his talk “The Underbelly of Drug Pricing.” Certainly, HOPA pharmacists deal with the financial toxicity of cancer drug therapies daily; the bigger policy questions that surround drug pricing and the overall cost of cancer care often seem overwhelming and beyond the control of any one of us in our daily practice. That is precisely why the PMP and HOPA’s Health Policy Committee are so important. Collectively, we can make a difference in offering solutions to these complex problems on a larger scale. 

In the last issue of HOPA News, I wrote about HOPA’s many new and ongoing collaborations with external groups, including our invitation to participate in former Vice President Biden’s Cancer Moonshot Summit. Our industry partners also recognize the importance of carefully evaluating various value frameworks—summarized so eloquently by HOPA member Kasia Shields, PharmD MBA BCOP BCPS, in her presentation at the PMP—to make sure that they include all the important data points that comprise the value proposition (for example, ensuring that the cost of drug therapies is included among the many aspects of cancer care that drive cost and ensuring that clinical domain experts participate in the creation of these tools). HOPA’s Health Policy Committee commented on the newest framework to be released by the Institute for Clinical and Economic Review (ICER); the letter can be found on our website at www.hoparx.org/images/hopa/advocacy/advocacy-activities/HOPA_Comments-ICER_Framework.pdf. The HOPA Board, Industry Relations Council (IRC) Workgroup, and IRC participants had a robust discussion about these issues as well as the issue of drug waste during the 6th annual IRC Summit held just before to the PMP.

I was pleased to represent HOPA at the Discern Health/American Society of Clinical Oncology roundtable on Improving Oncology Measurement for Accountable Care on September 16, where we collectively determined that our traditional measures of value are outdated and uninformative and that more attention needs to be given to including patient-reported outcomes in clinical trials and captured in medical records for practice-based research initiatives. On the same day, board member Ed Li represented HOPA at the National Comprehensive Cancer Network Biosimilar Summit, and on September 28 and 29, he represented us at the Institution for Clinical Immuno-Oncology and Association of Community Cancer Centers (ACCC) regional meetings; both meetings had elements of measuring value in cancer care as themes. It is important to ensure that the expertise and viewpoint of the oncology pharmacist continue to be included in those conversations. These collaborations are also an important way to effect large-scale changes in healthcare so that perhaps in the future, all practitioners in cancer care can spend more time on clinical practice and less time on administrative tasks to facilitate care. 

HOPA is excited to announce that after many years of discussion, we are going to venture into regional meetings. Rather than offer independent programming, we are partnering with ACCC to showcase HOPA programs that are both clinical and administrative as a way to connect with cancer center administrators (ACCC’s primary membership base) and demonstrate the value of the hematology/oncology pharmacist. Watch for the program to be held in March 2017 in Austin, TX. 

In support of the role of HOPA members in the value proposition in cancer care, we are pleased that four important task forces began their work in September. Three of these task forces were established to create tools and resources to support practice: the Entry-Level Competencies Task Force will establish outcome statements and create templates that will be helpful for training pharmacy students and PGY-1 pharmacy practice residents, the Pharmacist-Patient Partnership Task Force will create documents that patients can use to facilitate conversations with their pharmacist to help optimize their cancer treatment experience, and the Scope of Hematology/Oncology Pharmacy Practice Part II will update and add additional detail to the original 2010 document to better assist HOPA members in establishing roles, responsibilities, and new positions for their teams. The fourth task force, the Value of the Hematology/Oncology Pharmacist Task Force, will start its work soon and be responsible for conducting a literature review of hematology/oncology pharmacist services, identifying gaps in the literature, and proposing a research framework for HOPA to facilitate its research goal in the 2016–2020 Strategic Plan, to establish HOPA as a leader in research of hematology/oncology pharmacy intervention and impact.

The Board Certified Oncology Pharmacist (BCOP) Recertification Program continues to be a major endeavor, led by HOPA board members Ryan Bookout and Heidi Finnes and supported by dozens of dedicated HOPA members on the five committees in our BCOP infrastructure. We had 50 attendees at our Oncology Pharmacy Updates Course in Orlando in July and more than 50 attendees at the Conference Specialty Sessions Repeat at the PMP. We continue to evaluate the feedback from all the program offerings and value your input! Your constructive comments will help us make future programming even better. Now is a good time to take the tests that you’ve been putting off and to delve into the self-study course! 

Traveling with Chemotherapy

Lisa A. Thompson, PharmD BCOP
Clinical Pharmacy Specialist in Oncology
Kaiser Permanente Colorado
Lafayette, CO

Oral chemotherapy medications increasingly are used in the treatment of cancer, and many of these medications are taken on a continuous basis for extended durations.¹ Pharmacists frequently receive questions about traveling with medications, and these issues are especially relevant to patients receiving oral chemotherapy. 

General Considerations
Although pill organizers may be helpful to improve adherence, it is recommended that medications be stored in their original, pharmacy-labeled container when patients are traveling, in order to facilitate identification of these as prescription medications.² 

If taking an oral chemotherapy medication that must be refrigerated, patients should use a cooler or cold packs, with the medication itself stored in a manner that protects it from exposure to water (such as placing the prescription bottle in a waterproof container). Many hotels can provide an in-room refrigerator if needed; however, patients should contact the hotel in advance to confirm availability. 

Patients with travel plans frequently ask about dose timing when in different time zones. Patients traveling across multiple time zones may need to adjust the timing of their medication administration, taking into account the duration of their trip and their travel itinerary. For example, a patient traveling from Chicago to Berlin would need to account for a 7-hour time difference. If the patient typically takes his or her medication at 7 am and 7 pm in Chicago, he or she may choose to take the medication at 2 pm and 2 am in Berlin. Patients doing this may find it helpful to set a reminder alarm to prevent missed doses. Other patients may prefer to gradually adjust their dosage time before their trip. This is typically accomplished by taking the medication 1–2 hours earlier or later each day until the timing fits with their schedule in the destination city. Patients doing this should perform the gradual timing adjustment in reverse upon their return. Those taking oral chemotherapy medications should also travel with water and snacks if the medication should be taken with food, in order to prevent any delays in administration while traveling. 

Another important consideration relates to medication supply. In general, it is recommended that patients travel with enough medication for their planned trip and with additional supply to account for possible delays in their return. Given the high cost of many oral chemotherapy medications and differences in regulatory approval between countries, patients should not assume that they will be able to purchase their oral chemotherapy medication at their destination. Therefore, patients should work with their oncologist and prescription insurance provider to obtain a sufficient supply before their trip.

Air Travel 
Patients traveling by air should plan for some additional considerations, including location of their medication during travel and Transportation Security Administration (TSA) screening. Patients should pack their medications in their carry-on luggage to ensure that they have access to them in the event of lost checked baggage or flight delays. This also reduces the medication’s exposure to temperature extremes on the runway and in flight. 

As with other carry-on items, medications must undergo TSA screening. Liquid or topical medications are exempt from the “3-1-1 Liquids” rule; however, travelers should separate these items and inform TSA officers of their presence before beginning screening.2 Travelers should present liquid medications in excess of 3.4 ounces to TSA officers separately for screening. Medications stored at refrigerated temperatures may be transported with cold packs as long as they are identified to the TSA officers during the screening process. 

Although no harmful effects of consuming medications that have passed through X-ray security scanners are known,³ no information is available about the impact of these on medication integrity, and some passengers may prefer to have their medications screened using alternate screening procedures. This typically involves inspection by a TSA officer, which may be performed on request. Patients traveling with liquid medications or requesting alternate screening procedures should allow additional time for security screening. 

Automobile Travel 
Patients traveling by car should take extra care to ensure that their medication stays at an appropriate temperature. Medications that need refrigeration should be transported in a cooler. Patients also should use caution with medications that are stored at room temperature because the temperature in a parked automobile can fluctuate greatly in a short period of time. In general, patients should keep these medications on their person to prevent exposure to extreme heat or cold. 

International Travel 
Each country has unique requirements regarding traveling with medications and declaration of these upon entry. For instance, patients traveling to England may need to provide a signed letter from their prescribers listing their name, medications, and travel plans.⁴ Because of these variations, patients traveling internationally should research the requirements for their destination(s) well in advance of their planned travel. In general, it is recommended that patients travel with their medications in the original containers and obtain a recent prescription or provider’s note that includes the medication’s generic name and reason for use.⁵ 

Although international treaties do not allow for travelers taking narcotics or other controlled substances to travel with a supply for personal use,⁶ patients likely will need to complete some additional preparation prior to their travel. Depending on the laws and regulations of the destination country, patients may or may not need to present their controlled substances at border control, travel with prescriber documentation, or obtain a permit or certificate from their destination country. 

With the increasing use of oral chemotherapy, more patients with cancer are traveling with these medications. Pharmacists play a crucial role in educating patients; facilitating communication between the patient, providers, and insurers; and optimizing adherence during travel. 

References

1. Conti RM, Fein AJ, Bhatta SS. National trends in spending on and use of oral oncologics, first quarter 2006 through third quarter 2011. Health Aff (Millwood) 2014;33(10):1721-1727. 

2. Transportation Security Administration. Special procedures: disabilities and medical conditions. Retrieved from www.tsa.gov/travel/special-procedures. Accessed September 2016.

3. U.S. Food and Drug Administration. Frequently asked questions on cabinet X-ray systems. Retrieved from www.fda.gov/Radiation-EmittingProducts/RadiationEmittingProductsandProcedures/SecuritySystems/ucm116421.htm. Accessed September 2016. 

4. Drug and Firearms Licensing Unit. Travelling with controlled drugs. Retrieved from www.gov.uk/travelling-controlled-drugs. Accessed August 2016. 

5. U.S. Department of State Bureau of Diplomatic Security: Overseas Security Advisory Council. Traveling with medication. Retrieved from www.osac.gov/pages/ContentReportDetails.aspx?cid=17386. Accessed August 2016. 

6. International Narcotics Control Board. International guidelines for national regulations concerning travellers under treatment with internationally controlled drugs. Retrieved from www.incb.org/incb/en/psychotropic-substances/travellers_guidelines.html. Accessed August 2016. 

Personal Impact and Growth Reflection - Professional Guilt and the Moonshot

Sarah Scarpace Peters
PharmD MPH BCOP
Associate Professor of Pharmacy Practice
Albany College of Pharmacy and Health Sciences
Albany, NY

I was honored to attend then–Vice President Joe Biden’s Cancer Moonshot Summit at Howard University in Washington, DC, on June 29, 2016. It is not every day that you receive an e-mail from the office of the Vice President. I truly was so proud that HOPA had made it onto the Vice President’s radar. As an organization that was founded only 12 years ago and served initially as a forum for education, I was struck by how far we have come. HOPA has a robust advocacy and health policy agenda and has made many connections with pharmacy, patient, oncology, nursing, and industry organizations, and now, the Moonshot Summit.

Only 300 guests were invited to the Summit, representing stakeholders in cancer care even more diverse than the partnerships that HOPA now has established. When Jeremy Scott (one of HOPA’s government relations representatives from Drinker-Biddle who was instrumental in securing HOPA’s invitation to the event) and I arrived in the main conference room, tables in rounds of eight awaited us. There were no assigned seats, but placards with “#canserve” were prominently displayed as centerpieces on the “White House blue” tablecloths. The Vice President asked us to tweet our ideas about how we personally, or as the organization we represent, “#canserve” toward the goal of making 10 years of progress toward a cure in 5 years. I tweeted about how pharmacists #canserve by employing adherence strategies and managing side effects of treatment to keep patients on therapy longer, with better quality of life, until the next new breakthrough in treatment is available.

Jeremy and I were assigned to separate small-group sessions, each with approximately 20 participants. Both of my sessions involved passionate discussions and even some animosity between cancer prevention group representatives (Tobacco-Free Kids, American Cancer Society, and others) and those of us on the treatment side. I was personally and professionally conflicted as a HOPA representative and as someone who holds a master’s in public health with an epidemiology concentration (specifically focused in chronic disease and cancer epidemiology) and is aware that public health and preventative medicine initiatives are routinely underfunded when compared to investments in research and development for treatments (whether for cancer or any other disease state). The cancer prevention group representatives made the argument that more funding for primary prevention was the only pathway to “cure” cancer. We framed our efforts on secondary prevention and treating cancer as a chronic disease. Primary prevention through behavior change and policies focused on limiting environmental exposures are generally less expensive and can have many additional health benefits beyond cancer prevention than focusing on turning cancer into a chronic disease. 

The Vice President raised his voice only twice during the Summit: once to proclaim, “if there are angels in heaven, they are all nurses” in response to the excellent nursing care his son Bo had received during his cancer journey; and second to protest the high cost of cancer drugs, deepening my professional and even moral conflict. 

At the end of the day, I was walking down the stairs and heard someone call my name. Standing to the side was a woman whom I had met at an advisory board meeting almost a year earlier. The pharmaceutical company that ran that advisory board had the wisdom to invite patients to hear their perspectives on being treated. This patient was in one of my breakout sessions at the meeting, and I had gotten to spend time with her in a very small group. She had been diagnosed with stage IV lung cancer 3 years earlier, and she tearfully shared with us what it was like to live with a terminal illness and what treatment meant to her. She remembered me because she had no idea that hematology/oncology pharmacists were available to meet directly with patients to address their medication-related problems. That was the most profound advisory board meeting I had ever attended. And now here this patient was, with me again at this profound Moonshot Summit.

We talked for a bit about how she was doing and our impressions from the day. We shared the same sentiment about the broad scope of the Moonshot Summit and its unclear direction. In the end, though, she wanted to make sure that it was known that treatment matters—tolerable treatment, that is.

After speaking with her, I put my professional “guilt” about being on the treatment side of cancer aside and felt new hope and commitment that what I do—what all HOPA members do—matters to patients. In the August 20, 2016 issue of the Journal of Clinical Oncology, Bower and colleagues reported the results of a Swedish registry study that indicate that in the post-imatinib era, patients newly diagnosed with chronic myelogenous leukemia live almost as long as their age-matched peers (minus 3 years). It is my hope to read a similar paper for stage IV lung cancer in the next 20 years. It may be a Moonshot, but perhaps with the assistance of hematology/oncology pharmacists, patients like my new friend will stay on therapy longer with minimal adverse events as each new breakthrough descends from the research stars. 

What to Look For in Your First Job

Brandi Anders, PharmD BCOP
Hematology/Oncology Clinical Pharmacy Specialist
Wake Forest Baptist Health
Winston-Salem, NC

Morgan Belling, PharmD
Hematology/Oncology Clinical Pharmacist
University of Kansas Health System
Kansas City, KS

The time has come to start the search for that elusive, perfect first job. After countless hours of preparation and intensive years of training, you want a job that will allow you to use the knowledge and skill sets you have developed. You also seek a job that will allow you to practice in an area you are passionate about. With the many different options available, you might be wondering how to even begin. As two new practitioners who have just been through the process, we would like to offer some advice on things to consider when choosing your first position.

The critical first step is to take the time to do some soul-searching and determine what is most important to you. What makes you happy? What are you passionate about? What makes you get up in the morning and look forward to going to work day after day? Is it direct patient care, practicing in a certain subspecialty, leading as an administrator, training future pharmacy and medical professionals, serving as a residency program director, or conducting and publishing research? What are your personal and career goals for 1, 5, 10, and 20 years down the road? When you look back on your career, what specific, measurable accomplishments will make you most proud? Devote time to asking these questions and coming up with honest answers. Then make a list of considerations and prioritize them on the basis of what is most important to you. 

One of the most important details in the job search is the actual job description. Although it may seem like common sense, make sure you read the job description carefully and use the interview to clarify any concerns and get a better understanding of the position. What exactly will you be doing? What is the schedule? Whom will you be working with? What is expected of you? What opportunities or responsibilities exist for committee involvement? Is the position newly created, or has it been vacant for some time? How will your performance be assessed? Does the position have multiple components, such as clinical work, order verification, research, or teaching? How much time is devoted to each part? How long will you have to develop your practice before you will begin presenting to students and residents on rotation? What is the relationship between pharmacists and other members of the healthcare team? What role does the pharmacist play on the healthcare team? Does the position seem to offer a good work-life balance? Make sure you understand everything about the position so you know what you would be walking into. Does it match your interests, passions, and career goals? It is a good idea to ask pharmacists who work at the institution to describe their favorite aspect of practicing there. Also, if they could change one aspect of their position or institution, what would it be? These questions can offer a wealth of insight into whether your primary interests and goals align with those of the institution. 

Location is an important factor for many pharmacists when choosing between multiple positions. Do you want to be close to family and friends? Are you limited to a certain geographic region, or are you free to travel? Is this an area where you would consider starting and raising a family? Consider the climate. If you love having four seasons, then Florida might not be the best place for you. On the other hand, if you would prefer a warm climate year round, Minnesota is not your best option. Keep in mind that your first job likely will not be your last, and you probably won’t stay in the same place forever. However, it is important to remember that your first job can set the stage for the rest of your career as you continue to develop as a practitioner and establish working relationships with healthcare professionals from a variety of backgrounds and specialties who help mentor you.

Many consider salary the most important factor in choosing a potential job. Though salary should be taken into account, it should not be the only factor on which your decision is based. Salary should be adjusted for the cost of living in that geographic location. One might expect a higher salary in California than in Pennsylvania, but it is not as easy to estimate how much more you would need to earn for the salary to be considered comparable. Taxes also vary in geographic areas. Cost-of-living calculators can help with this aspect of the job search. Be sure to keep in mind the monetary value of benefits provided—from health insurance to the cost of parking. Taking all these things into account will allow you to compare net (or take-home) income, rather than just gross income. Although salary is important, it’s advisable to remember that you can’t put a price on job satisfaction.

Make sure that you understand the benefits provided by your potential employer. Do they offer medical, dental, and vision insurance? What are the retirement options available? Does the company offer a match on your retirement contributions? How long are you required to remain with the organization until you are fully vested? Many new practitioners may find it beneficial to meet with a financial advisor to help navigate these often unfamiliar aspects of a new job. Also, consider the sick and paid time off provided; are there separate pools for vacation and sick days, or do they come from the same pool? How many hours do you accumulate within each pay period? These are all things that should be considered when evaluating a new position.

You also will want to spend some time investigating the company climate and departmental leadership. Company climate refers to the energy, spirit, values, and culture of an organization as well as the relationships between people in the organization. What are the values of the organization? Is there good camaraderie among employees? Do they show respect to one another and seem to value each other’s ideas and opinions? Is there good communication within the department? Keep in mind that you are going to be spending a lot of time with your coworkers, so you want to imagine what it would be like working with them on a daily basis. Also consider the values of the department leadership. What is their vision for the department? What goals have they set? Do they invest in their employees’ ideas for improvement? Where do they see the department moving in the future, and do they have a plan to address the challenges that would hinder this progression? Remember that department leadership can directly influence the success and work environment of the whole department. 

Finally, you want to consider how you can continue to grow as a pharmacy professional within the organization. What programs are provided for professional development? Are you provided with seminar time and financial assistance to attend meetings? What opportunities are there for career growth and advancement? You want to make sure that you can continue to broaden your knowledge base and stay up to date with the pharmacy literature. It is important to identify and seek out mentors in the organization who can help you grow as an oncology pharmacist.

This list is certainly not comprehensive, and there may be other factors that you consider more or less important to you as an individual. But we hope that this will provide you with a reliable starting point when searching for your first job. Wherever you find yourself, always remember to keep the care and best interests of your patients first. Continue fostering your passion for oncology pharmacy and helping others. There is a reason you chose to practice in oncology; always remember that reason! It will motivate you for your lifetime. 

Intrathecal Chemotherapy: Focus on Drugs, Dosing, and Preparation

Mandy Gatesman, PharmD BCOP
Clinical Pharmacy Specialist, Hematology & Oncology
Virginia Commonwealth University Health System
Richmond, VA

Intrathecal (IT) administration of chemotherapy by lumbar puncture (LP) or intraventricular injection via Ommaya reservoir is used frequently in prophylaxis and treatment of a central nervous system (CNS) disease in both hematologic and solid tumor malignancies.¹ Nonetheless, there is a paucity of well-designed trials on the optimal dosing and preparation of these agents. Available guidelines primarily address safety aspects of IT chemotherapy dispensing.^2,3 The purpose of this review is to summarize the available literature on medications that can be given by the IT route for treatment of oncologic indications and attempt to address common questions regarding preparation and stability.

Intrathecal Medications for Oncologic Use
Methotrexate: Methotrexate is the most commonly used agent for IT administration. Dosing is based on age in pediatric patients (Table 1 - see PDF); the most common dose used in adults is 10–15 mg per injection. Methotrexate may be diluted to a concentration of 1 mg/ml using an appropriate sterile, preservative-free diluent;⁴ concentrations of up to 2.5 mg/ml also have been reported.⁵ Methotrexate is particularly vulnerable to light degradation, and care should be taken to protect any prepared methotrexate-containing product from light.⁶
For treatment of a CNS disease, IT methotrexate is commonly given twice weekly (every 2–5 days) for 4 weeks, then weekly for an additional 4 weeks; once-monthly maintenance dosing may then be administered.⁷ For prophylaxis of a CNS disease, the frequency of IT methotrexate varies and is usually dictated by the individual chemotherapy protocol.

Cytarabine: Similar to IT methotrexate, cytarabine also is dosed by age in pediatric patients (see Table 1); usual adult dose is 25–100 mg per injection. For treatment of a CNS disease, IT cytarabine may be given on the same schedule as IT methotrexate (twice weekly for 4 weeks, then weekly for 4 weeks, then once per month).7 Cytarabine may be diluted to a concentration of 0.4–20 mg/ml, but concentrations above 10 mg/ml may increase toxicity, perhaps because of the higher pH of the more concentrated product.⁵

A liposomal formulation of cytarabine (DepoCyt^®) prolongs the exposure of cytarabine in the cerebrospinal fluid, thereby allowing for less frequent administration (every 14 days). The dose of IT liposomal cytarabine is 35 mg in pediatrics and 50 mg in adults. Because of the risk of arachnoiditis with IT liposomal cytarabine, oral dexamethasone should be given for 5 days, starting the day of treatment.⁸ Unlike traditional cytarabine, liposomal cytarabine should not be mixed with any other medication in the same syringe (e.g., hydrocortisone). Liposomal cytarabine must be used within 4 hours of withdrawing from the vial.⁸

Cytarabine is commonly given in combination with methotrexate and a steroid as part of “triple IT therapy” (Table 2 - see PDF). For IT therapy consisting of cytarabine, methotrexate, and methylprednisolone, a study by D’Hondt and colleagues demonstrated stability for up to 12 hours when protected from light and stored in refrigeration.⁶ A recent study showed extended stability of cytarabine, methotrexate, and hydrocortisone when protected from light for up to 48 hours at room temperature and up to 5 days under refrigeration.⁹

Rituximab: Rituximab dosing for IT administration was assessed in a phase 1 dose-finding study. The dosing schedule was twice weekly (days 1 and 4) for 4 weeks; the study allowed a maximum of nine IT rituximab injections. The maximum tolerated dose was found to be 25 mg, which was prepared by diluting standard rituximab (10 mg/ml) with preservative-free sodium chloride to a final volume of 5 ml and injected over 1–5 minutes.10 Another phase 1 study investigated the tolerability of IT rituximab in combination with IT methotrexate for CNS lymphoma and confirmed 25 mg as the maximum tolerated dose. Treatment was administered twice weekly (days 1 and 4, +/- 1 day) for 4 weeks with IT rituximab given only on day 1 and IT rituximab followed by IT methotrexate (12 mg) given on day 4.11 Both studies used premedication prior to each IT rituximab dose with acetaminophen, diphenhydramine, and an H2 receptor antagonist. Response rates are reported in 40%–75% of patients with leptomeningeal involvement of lymphoma.^10,11

Trastuzumab: For management of leptomeningeal involvement of HER2+ breast cancer, IT trastuzumab has been employed in a variety of doses (range 4–150 mg) and schedules (every 7–21 days). It also has been used as monotherapy, in combination with systemic therapy, or in combination with other IT treatments (methotrexate, cytarabine, prednisone, thiotepa). Responses were noted in approximately two-thirds of patients.¹² Of note, Herceptin^® is supplied with bacteriostatic water, which contains the preservative benzyl alcohol, for reconstitution and injection. When the medication is prepared for IT administration, a diluent that does not contain preservative (e.g., sterile water for injection) must be used for reconstitution.¹³

Topotecan: IT topotecan has been used to treat primary CNS tumors and leptomeningeal disease in a variety of solid tumors (e.g., ovarian, breast, and lung tumors).^14,15 The usual dose as determined in a phase 1 trial is 0.4 mg twice weekly (every 3–4 days) for 4–6 weeks, then weekly for 4–6 weeks; maintenance therapy can then be administered twice monthly for 4 months, then once monthly thereafter for up to 8 months.^14,16 Each dose may be prepared using preservative-free topotecan diluted with preservative-free sodium chloride to a final volume of 4–10 ml and injected over ~5 minutes.^15,16 Reported responses to IT topotecan in leptomeningeal disease are 21%–33%; responses seem to be higher in primary CNS tumors (~80%).¹⁵

Thiotepa: Thiotepa is less commonly administered via the IT route and has shown limited success, potentially because of its rapid clearance from the CSF.17 When used for treatment of a CNS disease, IT thiotepa has been given as a flat dose of 10 mg or a body-surface-area-based dose of 5–12 mg/m2.^17,18 The schedule also varies from weekly¹⁷ to twice weekly,¹⁸ but thiotepa may be given on the same schedule as IT methotrexate or cytarabine (twice weekly for 4 weeks, then weekly for 4 weeks, then once a month).⁷

Miscellaneous Agents: Etoposide and interferon also have been used for IT administration.¹ Etoposide has been used at a dose of 0.5 mg daily for 5 days, repeated every other week for 8 weeks, with approximately 25% response rates reported in a mixed population of solid tumors and lymphoma.¹⁹ Interferon alfa-2b was studied at a dose of 1 million units three times weekly (given every other day) for 4 weeks, then three times per week every other week for 4 weeks, then three times per week every month for 4 months. Higher responses were noted in patients with hematologic malignancies (chronic myeloid leukemia and non-Hodgkin lymphoma). Arachnoiditis was common (73%) but mostly grade 1; of note, steroids were not used to prevent or treat arachnoiditis because of the concern of compromising interferon efficacy.²⁰ Because of the high risk of neurotoxicity, the National Comprehensive Cancer Network rates interferon alfa-2b as a category 2B option for IT therapy.¹

Intraventricular Versus Intralumbar Administration
Delivery of medications directly into the CSF can occur by either LP or direct administration into the ventricles via a subcutaneous access device such as an Ommaya reservoir. Both have risks and benefits. The risks include patient discomfort and the inconvenience of repeated LPs for the intralumbar route and the risk of infection with placement of an Ommaya reservoir. Regardless of which method is used, drug clearance of most agents, including methotrexate and cytarabine, is directly related to the rate of CSF bulk flow excretion rather than usual mechanisms of drug metabolism.²¹

There is high interpatient variability of ventricular concentration of methotrexate following intralumbar administration.²² If the intralumbar route of administration is chosen, patients should remain in the prone position for at least 1 hour following injection to maximize drug distribution throughout the CSF and into the ventricular space.²³

Intrathecal Chemotherapy Toxicity
Toxicity following IT chemotherapy may include nausea or vomiting, arachnoiditis (headache, back pain, nuchal rigidity, fever), and chronic leukoencephalopathy (confusion, somnolence, ataxia, seizures).⁴ The Children’s Oncology Group recommends removing enough CSF to equal at least 50% of the volume of the administered IT product to decrease the risk of neurotoxicity associated with IT therapy. Liposomal cytarabine may be associated with higher risk of neurotoxicity than standard triple IT therapy.^24,25 Patients previously treated with IT chemotherapy may be at increased risk for neurotoxicity from nelarabine.²⁶ Vinca alkaloids (vincristine, vinblastine, vinorelbine) are fatal if given intrathecally and should be mixed in minibags or labeled appropriately.³

Headache also may occur as a result of the LP procedure itself, presumably because of a leakage of CSF through the puncture site. The headache usually is constant, worsens within 15 minutes of standing, and is relieved within 15 minutes of lying down. Bed rest and analgesics are primary treatments, but if the headache persists for more than 72 hours, alternative treatments may be initiated.²⁷ Caffeine and sodium benzoate significantly improve the symptoms of post-LP headache when given at a dose of 500 mg in 1,000 ml normal saline over 1 hour.²⁸ Gabapentin, hydrocortisone, and theophylline also have demonstrated benefit. Nonpharmacologic interventions may include an epidural blood patch to block the leakage of CSF if the condition is refractory to drug therapy.²⁷

Preparation: Other Considerations
Regardless of which agent is being used, only preservative-free products and diluents should be used for IT administration because of the risk of neurotoxicity with preservatives such as benzyl alcohol. Diluents for reconstitution may include preservative-free 0.9% sodium chloride, lactated Ringer’s solution, or Elliot’s B solution. The volume of the finished product varies significantly but often is in the range of 3–10 ml. Stability often is drug specific, but preparation as close to the time of administration as possible is prudent. 

One question commonly encountered is the use of a filter in preparing IT chemotherapy products. Theoretically, filtration would be used to remove microorganisms such as bacteria and fungus, which would require a ≤0.2-micron filter. United States Pharmacopeia (USP) chapter 797 accepts filtration as a form of sterilization only for high-risk, compounded products. IT products prepared using aseptic technique in an appropriate ISO class 5 environment would be considered low or medium risk; filtration is not specifically addressed for those classifications.²⁹ No data exist regarding the use of filtration specifically for IT products. Larger molecules, such as the monoclonal antibodies (rituximab, trastuzumab) and liposomal cytarabine, should not be filtered because of the large size of the molecule.⁸

References

1. National Comprehensive Cancer Network. Central nervous system cancers (version 1.2106). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed September 3, 2016.

2. Neuss MN, Polovich M, McNiff K, et al. 2013 updated American Society of Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards including standards for the safe administration and management of oral chemotherapy. J Oncol Pract. 2013;9(2 Suppl):5s-13s.

3. Goldspiel B, Hoffman JM, Griffith NL, et al. ASHP guidelines on preventing medication errors with chemotherapy and biotherapy. Am J Health Syst Pharm. 2015;72(8):e6-e35.

4. Methotrexate [package insert]. Carolina, PR: Lederle Parenterals Inc; 2003.

5. de Lemos ML, Monfared S, Denyssevych T, et al. Evaluation of osmolality and pH of various concentrations of methotrexate, cytarabine, and thiotepa prepared in normal saline, sterile water for injection, and lactated Ringer’s solution for intrathecal administration. J Onc Pharm Pract. 2009;15(1):45-52.

6. D’Hondt M, Vangheluwe E, Van Dorpe S, et al. Stability of extemporaneously prepared cytarabine, methotrexate sodium, and methylprednisolone sodium succinate. Am J Health-Syst Pharm. 2012;69(3):232-240.

7. Chamberlain MC. Leptomeningeal metastasis. Curr Opin Neurol. 2009;22(6):665-674.

8. DepoCyt [package insert]. Gaithersburg, MD: Sigma-Tau Pharmaceuticals, Inc; 2014.

9. Olmos-Jimenez R, Espuny-Miro A, Diaz-Carrasco MS, Fernandez-Varon E, Valderrey-Pulido M, Carceles-Rodriguez C. Stability of four standardized preparations of methotrexate, cytarabine, and hydrocortisone for intrathecal use. J Oncol Pharm Pract. 2016;22(5):659-665.

10. Rubenstein JL, Fridlyand J, Abrey L, et al. Phase 1 study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol. 2007;25(11):1350-1356.

11. Rubenstein JL, Li J, Chen L, et al. Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma. Blood. 2013;121(5):745-751.

12. Zagouri F, Sergentanis TN, Bartsch R, et al. Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis. Breast Cancer Res Treat. 2013;139(1):13-22. 

13. Herceptin [package insert]. San Francisco, CA: Genentech, Inc; 2016.

14. Groves MD, Glantz MJ, Chamberlain MC, et al. A multicenter phase 2 trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol. 2008;10(2):208-215. 

15. Gammon DC, Bhatt MS, Tran L, Van Horn A, Benvenuti M, Glantz MJ. Intrathecal topotecan in adult patients with neoplastic meningitis. Am J Health Syst Pharm. 2006;63(21):2083-2086.

16. Blaney SM, Heideman R, Berg S, et al. Phase 1 clinical trial of intrathecal topotecan in patients with neoplastic meningitis. J Clin Oncol. 2003;21(1):143-147. 

17. Fisher PG, Kadan-Lottick NS, Korones DN. Intrathecal thiotepa: reappraisal of an established therapy. J Pediatr Hematol Oncol. 2002;24(4):274-278.

18. Grossman SA, Finkelstein DM, Ruckdeschel JC, Trump DL, Moynihan T, Ettinger DS. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. J Clin Oncol. 1993;11(3):561-569.

19. Chamberlain MC, Tsao-Wei DD, Groshen S. Phase 2 trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer. 2006;106(9):2021-2027.

20. Chamberlain MC. A phase 2 trial of intra-cerebrospinal fluid alpha interferon in the treatment of neoplastic meningitis. Cancer. 2002;94(10):2675-2680.

21. Fleischhack G, Jaehde U, Bode U. Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis. Clin Pharmacokinet. 2005;44(1):1-31.

22. Shapiro WR, Young DF, Mehta BM. Methotrexate: distribution in cerebrospinal fluid after intravenous, ventricular, and lumbar injections. N Engl J Med. 1975;293(4):161-166.

23. Blaney SM, Poplack DG, Godwin K, McCully CL, Murphy R, Balis FM. Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration. J Clin Oncol. 1995;13(1):177-179.

24. Bassan R, Masciulli A, Intermesoli T, et al. Randomized trial of radiation-free central nervous system prophylaxis comparing intrathecal triple therapy with liposomal cytarabine in acute lymphoblastic leukemia. Haematologica. 2015;100(6):786-793.

25. Jabbour E, O’Brien S, Kantarjian H, et al. Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia. Blood. 2007;109(8):3214-3218.

26. Arranon™ [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011.

27. Basurto Ona X, Osorio D, Bonfill Cosp X. Drug therapy for treating post-dural puncture headache. Cochrane Database Syst Rev. 2015;(7):CD007887.

28. Zeger W, Younggren B, Smith L. Comparison of cosyntropin versus caffeine for post-dural puncture headaches: a randomized double-blind trial. World J Emerg Med. 2012;3(3):182-185.

29. American Society of Health-System Pharmacists. ASHP guidelines on compounding sterile preparations. Am J Health Syst Pharm. 2014;71(2):145-166. 

Review of Anticoagulants in Patients with Cancer:
A Focus on Oral Anticoagulants

Christina Davis, PharmD
PGY2 Oncology Pharmacy Resident
University of Colorado Anschutz Medical Campus
Aurora, CO

Cancer-associated venous thromboembolism (VTE) accounts for a significant degree of morbidity and mortality. Patients with cancer are at a several-fold increased risk for VTE compared to their counterparts without cancer, with an overall incidence of VTE between 4% and 20%.¹ High-risk factors for developing VTE in this population include primary site of malignancy (e.g., lungs, pancreas, brain, gastrointestinal system, women’s reproductive organs, kidneys, blood and lymphatic systems), time since diagnosis (risk is higher within the first 3–6 months), advanced stage of disease development, type and intensity of chemotherapy (e.g., hormonal therapy, use of antiangiogenesis agents, high-dose dexamethasone), exposure to radiation therapy, ethnicity (risk is higher among African Americans), and the presence of comorbidities.^1,2 This clinical picture of hypercoagulability is further complicated by the fact that patients with cancer also experience a higher rate of bleeding than the general population. It is reported that thrombocytopenia occurs in approximately 10% of cancer patients.³ This is most commonly a result of bone marrow or blood vessel infiltration by the tumor and abnormalities in platelet function or coagulation factors, which can be a result of liver dysfunction, chemotherapy, or radiation.³

Despite this increased risk of VTE in patients with cancer, there are little data to support routine thromboprophylaxis in the outpatient setting. Certain high-risk patients, such as those with multiple myeloma receiving lenalidomide or thalidomide in combination with dexamethasone or chemotherapy, are the exception, and for them prophylaxis with either a low-molecular-weight heparin (LMWH) or low-dose aspirin is recommended. Guidelines agree that most hospitalized patients with active cancer and those undergoing major cancer surgery require VTE prophylaxis in the absence of a contraindication to anticoagulation (Table 1 - see PDF).^1,2

LMWH is the agent of choice for the initial 5–10 days of treatment of established deep vein thrombosis (DVT) or pulmonary embolism (PE) and for long-term secondary prophylaxis for at least 3–6 months.1 This recommendation was established based on the results of the Clots in Legs or sTockings (CLOT) trial, during which patients with active cancer and newly diagnosed symptomatic DVT/PE were randomized to receive either dalteparin 200 units/kg daily for 1 month followed by 100 units/kg daily for a total of 6 months or warfarin with a target international normalized ratio (INR) of 2–3. The results showed a statistically significant reduction in the primary outcome of recurrent VTE in patients who received dalteparin, with no significant difference in bleeding risk or overall survival at 6 months.⁴ Although no trials have directly compared the efficacy of other LMWH products, such as enoxaparin, to warfarin, many clinicians feel that this advantage can be extrapolated to other LMWH agents. Potential advantages of LMWHs that may contribute to their superior efficacy over vitamin K antagonists (VKA) include a more predictable dose-response curve, lack of need for routine therapeutic monitoring, and minimal dependence on genetic and environmental factors.⁵ Despite these advantages, aspects such as cost and unwillingness or inability to self-administer injections may make many patients hesitant about initiating therapy with LMWH.

A meta-analysis from 2011 compared the efficacy and safety of unfractionated heparin (UFH), LMWH, and fondaparinux for the initial treatment of VTE in patients with cancer. Results from this study showed a statistically significant reduction in mortality at 3 months follow-up with LMWH compared to UFH but did not show a difference in VTE recurrence. There was no difference in mortality, VTE recurrence, or major or minor bleeding with UFH compared to fondaparinux.⁶ On the basis of this information and the lack of routine monitoring needed, LMWHs are considered first-line treatments for the acute management of VTE in cancer patients (see Table 1).

Because of the lack of clinical experience regarding safety and efficacy in cancer patients, direct oral anticoagulants are not recommended in current guidelines for acute or chronic management of VTE (see Table 1). In the landmark trials that evaluated these agents for the treatment of VTE, the percentage of patients with active cancer was very small, ranging from 2.5% to 6% (Table 2 - see PDF). However, direct oral anticoagulants (DOACs) have many potential advantages that make their use attractive to providers. These include their wide therapeutic window, rapid onset and offset, lack of routine monitoring, predictable pharmacokinetics, and relatively few drug and diet interactions when compared to warfarin.⁷ A meta-analysis published in Chest in 2015 compared DOACs to conventional anticoagulants (heparin followed by VKA) for the treatment of cancer-associated VTE.⁸ Six studies were included in the analysis: two with dabigatran, two with rivaroxaban, one with apixaban, and one with edoxaban (Table 2 - see PDF). VTE recurrence and major bleeding rates in patients with cancer were reported to be 3.9% and 3.2% in the DOAC group versus 6% and 4.2% in the conventional anticoagulation group. This demonstrated a nonsignificant but favorable trend in reduction of recurrent VTE and no apparent increased risk of bleeding with the use of DOACs. This reduction was consistent across all of the studies used in the analysis.⁸ However, no clinical trials are currently available comparing these agents to LMWHs, which are the preferred first-line treatment for VTE in patients with cancer.

Several clinical factors must be considered when choosing the most appropriate anticoagulant for a patient. These include absolute contraindications to anticoagulant therapy, overall bleeding risk, renal function, cost, and burden of treatment (e.g., self-injecting, frequency of monitoring). It is also important to recognize potential drug-drug interactions between DOACs, chemotherapy, and common supportive-care medications. All of the DOACs are substrates of P-glycoprotein (P-gp) and both rivaroxaban and apixaban are major substrates of CY3A4, making avoidance of strong CYP 3A4 inhibitors/inducers imperative. Certain chemotherapy and targeted agents (e.g., dasatanib, ibrutinib, bevacizumab) also can put a patient at higher risk of bleeding and must be considered when assessing risk versus benefit of anticoagulation. One major clinical consideration is the availability of a reversal agent in the event of a life-threatening bleed or emergency surgery. Protamine is the agent of choice for reversal of UFH or LMWH (Table 3 - see PDF) and must be administered by slow intravenous infusion (no faster than 5 mg/min) because of the risk of anaphylaxis.² Reversal strategies for warfarin are stratified according to the patient’s INR and the presence of bleeding or need for emergent surgery. In regard to DOACs, dabigatran is the only agent with a specific antidote with a cost of $4,200 per 5-gram dose of idarucizumab. Antidote availability, quality of evidence, and patient-specific factors should be considered when assessing the risk versus benefit of anticoagulation in patients with cancer. 

References

1. Lyman GH, Bohlke K, Khorana AA, et al. (2015) Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update 2014. J Clin Oncol. 33:654–656.

2.  Streiff MB, Holmstrom B, Ashrani A, et al. NCCN clinical practice guidelines in oncology: Cancer-Associated Venous Thromboembolic Disease, Version 1.2016. J Natl Compr Canc Netw. 2016 July. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf

3. Pereira J, Phan T. Management of bleeding in patients with advanced cancer. Oncologist. 2004;9(5):561-70.

4. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53

5. Zacharski LR, Prandoni P, Monreal M. Warfarin versus low-molecular-weight heparin therapy in cancer patients. Oncologist. 2005 Jan;10(1):72-9.

6. Aki EA, Vasireddi SR, Gunukula S, et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev. 2011 Jun 15;(6):CD006649. 

7. Bauer KA. Pros and cons of new oral anticoagulants. Hematology Am Soc Hematol Educ Program. 2013;2013:464-70.

8. Vedovati MC, Germini F, Agnelli G, Becattini C. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest. 2015 Feb;147(2):475-83. 

9. Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808

10. Bauersachs R, Berkowitz SD, Brenner B, et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-510

11. Büller HR, Prins MH, Lensin AW, et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97.

12. Büller HR, Décousus H, Grosso MA, et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-15.

13. Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-52.

14. Schulman S, Kakkar AK, Goldhaber SZ, et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-72.

Chemotherapy Stewardship: Managing Patient
Outcomes and Healthcare Costs

Peter Campbell, PharmD BCOP
Clinical Pharmacy Manager, Hematology/Oncology
New York Presbyterian Hospital/Columbia University Medical Center
New York, NY

The cost of medical care in the United States is increasing at an alarming rate, and the cost of cancer care is becoming a larger percentage of overall medical care spending. It is estimated that by 2020, the cost of cancer care will be higher than $157 billion—representing a 27% increase from 2010 spending.¹ A portion of the increased cost of cancer care is directly related to the increasing prices of chemotherapeutic and targeted therapies used in the treatment of various cancers. Prior to the year 2000, the average cost for 1 year of chemotherapy treatment was approximately $10,000. Now a large percentage of recently approved chemotherapeutic agents exceed $100,000 for 1 year of treatment.²

As the cost of cancer care becomes increasingly burdensome, many institutions are pursuing means through which to reduce costs. Though stewardship efforts in fields such as infectious diseases have improved outcomes and reduced costs, no universal stewardship approaches have been applied to the field of oncology. Strategies that have been applied to reduce chemotherapy costs and promote chemotherapy stewardship include restricting agents to outpatient settings (including inpatient- and outpatient-specific formularies), utilization of regimen-specific order sets, and multidisciplinary input during treatment decisions.³

Institutions frequently use formulary restrictions or preferred-drug lists to control the prescribing and administration of expensive medications. Formulary restrictions have been shown to be an effective method to reduce the cost of medications but have not been proven to reduce overall drug expenditures.⁴ Though having specific preferred chemotherapeutic agents on the formulary may help to reduce medication costs, additional restrictions to outpatient administration only may further improve medication cost savings. The restriction of certain chemotherapeutic agents to outpatient-only administration may allow for a more favorable reimbursement, as opposed to the significant costs that can frequently be associated with an inpatient admission for chemotherapy administration. 

An alternative to outpatient formulary restrictions is the development of separate inpatient and outpatient medication formularies. A downside that may be associated with two institutional formularies is the increased cost of staff time necessary to manage, maintain, and enforce the respective formularies. With a knowledge base of chemotherapeutic regimens that may be safely and effectively administered in an outpatient setting, pharmacists can play an active role in formulary restriction and management. 

Another method of controlling chemotherapy costs is through the use of electronic chemotherapy order sets. The use of order sets has long been linked to improved chemotherapy administration safety. The safe administration of chemotherapy can assist in cost reduction through the elimination of additive spending that results from medical errors, which totaled $19.5 billion in 2008.⁵ Although electronic chemotherapy order sets have widely been shown to improve the safety of chemotherapy administration, they may also be used to increase the appropriateness of chemotherapy administration. With order sets, providers are steered toward prescribing preferred formulary agents, which often have been determined to be cost-effective options by the Formulary and Therapeutics Committee. Order sets also allow certain medications to be restricted to certain providers through privileges, which can prohibit the ordering of inappropriate medications according to U.S. Food and Drug Administration (FDA) or institutional approvals. Electronic chemotherapy order sets also allow for the auditing and review of chemotherapy ordering and administration. By using order sets as a source of data, institutions are able to more easily review their chemotherapy prescribing and administration practices. These reviews make it possible for institutions to make necessary changes to policies and guidelines in order to administer chemotherapy in a more cost-effective manner. 

Obtaining multidisciplinary input during treatment decisions may also be used to reduce chemotherapy costs. Antimicrobial stewardship has been proven to be a successful method for improving outcomes and reducing costs in the treatment of infectious diseases, with pharmacists often playing an integral role.⁶ In a survey conducted among U.S. and Canadian oncologists, the majority of practitioners favored the use of more cost-effectiveness data in treatment decisions, but few felt comfortable with interpreting and applying these cost-effectiveness data.⁷Though most physicians are adequately equipped with the knowledge to make evidence-based treatment decisions, pharmacists may be able to supplement the clinical knowledge base and cost-effectiveness aspects of treatment. Pharmacists can use their clinical knowledge to recommend less expensive treatments that have been shown to have similar efficacy. 

As cancer treatment continues to evolve and increase in price, institutions are continually forced to re-evaluate their methods of chemotherapy prescribing and administration. Several methods may assist institutions in controlling costs, and pharmacists are in a prime position to help develop and carry out these methods. With pharmacists having been used successfully to develop antimicrobial stewardship programs, their role in chemotherapy stewardship may help control the ever-rising cost of chemotherapy while optimizing patient outcomes.

References

1. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010–2020. J Natl Cancer Inst. 2011;103:117-28.

2. Kantarjian H, Steensma D, Sanjuan JR, et al. High cancer drug prices in the United States: reasons and proposed solutions. J Oncol Pract. 2014;10:e208-11. 

3. Li E, Schlief R, Edelen B. Hospital management of outpatient oncology treatment decisions: a survey to identify strategies and concerns. J Oncol Pract. 2013;9:e248-54.

4. Carlton RI, Bramley TJ, Nightengale B, et al. Reviews of outcomes associated with formulary restrictions: focus on step therapy. Am J Pharm Benefits. 2010;2:50-8.

5. Andel C, Davidow SL, Hollander M, et al. The economics of healthcare quality and medical errors. J Health Care Finance. 2102;39:39-50.

6. Paskovaty A, Pflomm JM, Myke K, et al. A multidisciplinary approach to antimicrobial stewardship: evolution into the 21st century. J Antimicro. 2005;25:1-10.

7. Berry SR, Bell CM, Ubel PA, et al. Continental divide? the attitudes of US and Canadian oncologists on the costs, cost-effectiveness, and health policies associated with new cancer drugs. J Clin Oncol. 2010;28:4149-53.

Helpful Hints for Successful Grant Submissions

Lisa M. Holle, PharmD BCOP FHOPA
Associate Clinical Professor
UConn School of Pharmacy
Department of Pharmacy Practice

Hai T. Tran, PharmD
Associate Professor
UT MD Anderson Cancer Center
Divisions of Cancer Medicine & Pharmacy

When you have a research idea with a reachable goal that improves current available options, the next step is to identify possible sources of funding. A variety of resources are potential sources of support for your research project. Often, you do not have to look beyond your institution, especially if you are working at a research-focused center. Often each quarter or each year, small institutional grants that can support small projects are available. These are referred to as “seed grants” to help investigators acquire preliminary data to build upon for larger, career-building types of grants, such as those funded by the National Institutes of Health. Other sources of funding include healthcare organizations such as HOPA, American Society of Health-System Pharmacists, American College of Clinical Pharmacy, American Cancer Society, American Society of Clinical Oncology, American Association for Cancer Research, and American Society for Clinical Pharmacology and Therapeutics. In addition, disease-specific foundations such as the Susan G. Komen Breast Cancer Foundation, LUNGevity, National Pancreatic Cancer Foundation, and Leukemia and Lymphoma Society provide research funding. Some even smaller groups within your local area or state may support research; these are typically set up by family members or friends as memorials. Each has specific guidelines, target audiences, and goals, and the application requirements vary greatly; you should therefore read the grant announcement carefully and always contact the grant administrator directly to help you with your letter of intent and application. Remember to start early.

The Letter of Intent 

Many foundation-sponsored grants require a letter of intent to allow the foundation to quickly assess whether the proposed project is a good match with the foundation’s interests. For those projects that appear to be a good match, the foundation will typically invite submission of a full proposal for review. Letters of intent must be concise yet engaging. You should avoid jargon, adjectives, and flowery subjective statements that are not supported by facts. Instead, the letter should make a logical persuasive argument outlining how your project can solve a significant problem or gap in knowledge. The letter of intent is typically a condensed version of the proposal, generally 2–3 pages in length. It is important to thoroughly review the criteria for the letter, follow all directions as written, and stay within the page and word limits. Not following directions can lead to automatic rejection. Common components of letters of intent include the following:

Opening (typically one paragraph)
This section should succinctly describe what you want to do, such as answering who wants to do what, how much funding is being requested, and over what time period. The reader should have a good understanding of the request just by reading this paragraph.

Statement of Need: the “why” of the project
(typically one or two paragraphs)

Project Activity: the “what” and “how” of the project
(typically the bulk of the letter)
This section should provide an overview of activities and details (as space allows), highlight your innovative approach, and explain why this proposal deserves funding. In this section you would also describe any collaborations with other institutions and the roles of those collaborators. Keeping a tight goal-oriented timeline helps to show that the proposal can be completed within the specified time. 

Outcomes (typically one or two paragraphs)
This section describes the specific outcomes you will work toward and how you are evaluating the project (i.e., how you know you’ve achieved your goal). These outcomes should be specific and measurable within the construct of the grant.

Research Team Credentials (typically one paragraph)

Budget (typically one paragraph)
This section provides a general description of the project funding and the total amount of funds requested. Each grant provides some guidelines, but always keep in mind that the reviewers are aware of cost. Thus, salary figures should be appropriate for the individuals supported by the grant and should not overlap with support from another funding source.

Closing (typically one paragraph)
This section provides the contact name and information for the grant requestor and expresses appreciation for the reader’s attention and the opportunity to submit a response (if this is a request for proposal [RFP]) or specifically indicates your interest in discussing the project (if not in response to an RFP). 

ISOPP Celebrates 20 Years

Rowena Schwartz, PharmD BCOP
Associate Professor of Pharmacy
University of Cincinnati
Cincinnati, OH

The International Society of Oncology Pharmacy Practitioners (ISOPP) began celebrating its 20th anniversary in 2016. Helen McKinnon, founder and first president of ISOPP, said ISOPP brings together dedicated professionals to “share their knowledge, support clinical research and improve cancer treatment for patients around the world.” After visiting oncology pharmacists in the United States and the United Kingdom in 1986, McKinnon hosted the first International Symposium on Oncology Pharmacy Practice in New Zealand in 1988. After a successful meeting, a group of dedicated oncology pharmacists from around the globe decided to continue the meetings and ultimately formed an international society for oncology pharmacy. ISOPP was incorporated as an organization in 1986. Many changes have occurred over the last 20 years, but ISOPP continues to be the forum for oncology pharmacists from around the world to work together to advance cancer care. 

As ISOPP began its 20th anniversary celebration, it also took a close look at the organization and developed a plan for the future. ISOPP reached out to members, partners, and past leaders for thoughts on its mission and a strategic plan. The strategic plan presented to members at the annual meeting in Santiago, Chile, in April 2016 confirmed ISOPP’s vision to advance oncology pharmacy care for patients throughout the world. ISOPP aims to improve the lives of those touched by cancer by advancing oncology pharmacy care throughout the world through engagement and mobilization of the oncology pharmacy community. The strategic plan for ISOPP focuses on efforts to increase engagement and mobilization of the world’s oncology pharmacy community to advance cancer care.

Many ISOPP members live in countries or areas of the world with flourishing communities of oncology pharmacists. ISOPP provides a forum for these communities to collaborate and advance oncology pharmacy services throughout the world. ISOPP continues to reach out globally to areas where oncology pharmacy is new or facing challenges, and uses the expertise of oncology pharmacists around the globe to help develop oncology pharmacy where needed.

I was introduced to ISOPP when a friend invited me to attend an oncology pharmacy meeting in Hamburg, Germany. I had never attended an International Symposium on Oncology Pharmacy Practice meeting and was unaware of the efforts to form an international oncology pharmacy organization. The ISOPP meeting in Germany changed my approach to oncology pharmacy. I realized that my worldview was relatively small. There were, and still are, incredible individuals throughout the world who are working to advance oncology pharmacy and cancer care. ISOPP introduced me to these individuals.  

ISOPP thrives on the contributions of individual members. The most fulfilling benefit of ISOPP membership is the opportunity to contribute to its mission. ISOPP has provided me with both a broader understanding of oncology pharmacy and the chance to collaborate with practitioners in other countries. Through my work with ISOPP, I have met people who both inspire and teach me. 

I also attended the oncology pharmacy meeting in the United States where the idea of a Hematology and Oncology Pharmacy Association (HOPA) was first introduced. I was excited to see a forum for oncology pharmacy practitioners from the United States. Working with ISOPP, I knew many countries had strong national oncology pharmacy organizations and was excited to see an organization dedicated to the unique needs of oncology pharmacy in the United States. I am also optimistic about the many opportunities for HOPA to work with ISOPP and oncology pharmacists from around the world to advance cancer care. 

One of the best ways to learn about ISOPP is to attend an ISOPP meeting. In 2016 ISOPP held its symposium in South America for the first time. This celebration of oncology pharmacy was hosted by dedicated and committed oncology pharmacists from Chile. In 2017 we head to Europe for ISOPP XVI in Budapest, Hungary, on April 26–29. Visit www.isopp2017.org to learn more about the program, and visit www.isopp.org to learn more about the available opportunities to contribute to oncology pharmacy globally. 

Immunotherapy Resistance

Shelly E. Hummert, PharmD
Clinical Oncology Pharmacist
Huntsman Cancer Institute, University of Utah
Salt Lake City, UT

In the last decade, approaches to using the immune system to treat cancer have exploded. Currently, immunotherapy is an important U.S. Food and Drug Administration–approved option for the management of melanoma, lung cancer, and renal cell carcinoma. Based on the results in these disease states, immunotherapy continues to be studied in a range of cancers and has the potential to become the backbone of treatment to effectively control cancer.  

A benefit of immunotherapy is the possibility of a durable response. This has been attained with interleukin-2 and immune-modulating antibodies such as ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 inhibitor, and pembrolizumab and nivolumab, programmed death 1 (PD-1) inhibitors. In a study conducted by Postow, first-line therapy with ipilimumab in advanced melanoma was compared to combination therapy with ipilimumab and nivolumab in advanced melanoma.¹ A median duration of response was not identifiable at the conclusion of the study because the majority of patients (75% of patients receiving ipilimumab alone and 82% of patients receiving combination therapy) continued to have an ongoing response. 

However, the possibility of resistance to immunotherapy, as with any type of treatment, remains a concern. Ribas recently demonstrated that only 74% of patients who achieved an objective response with pembrolizumab maintained the response at 21 months, indicating that 26% of these patients experienced disease progression.² Zaretsky and colleagues found similar results, with 36% of patients demonstrating disease progression after obtaining an objective response with pembrolizumab.³ The initial response to treatment and median progression around 21 months led the researchers to postulate that relapse was a result of clonal selection. 

Zaretsky and colleagues compared tumor DNA samples at baseline and relapse in four patients. Of the four patients assessed, differences between the DNA samples were linked to loss of heterozygosity.³ Loss-of-function mutations in the Janus kinase 1 and 2 (JAK1 and JAK2) were identified in two of the four patients. These mutations were associated with the interferon-receptor pathway and were acquired through the loss of the wild-type chromosome and duplication of the mutated allele. Analysis of the baseline biopsies demonstrated response to interferon alfa, beta, and gamma, whereas analysis of the relapse biopsies demonstrated no response to interferon gamma. Interferon gamma is responsible for cell growth inhibition. These data suggest that loss of JAK mutations may lead to a decrease in antigen presentation and expression of programmed death–ligand 1 (PD-L1), enabling the tumor to evade recognition by the immune system. 

An acquired resistance because of a mutation in the gene encoding beta-2-microglobulin (β2M), a component of the major histocompatibility complex class I, was identified in a third patient who developed relapsed disease in the Zaretsky trial.³ Antitumor T cells recognize antigens presented on cell surfaces by MHC class I molecules, which are limited or eliminated by mutations in β2M.⁴ Restifo and colleagues also concluded that the loss of β2M in five metastatic melanoma patients was a result of immunotherapy treatment and may be a mechanism of acquired immuno-
resistance.⁵

The fourth patient who developed relapsed disease did not have a loss of heterozygosity.³ However, neither the baseline nor the relapse biopsies expressed PD-L1, indicating the possibility of altered expression of interferon-inducible genes as an alternative mechanism of resistance.  

Other possibilities for mechanisms of resistance that have been hypothesized include expression of suppressive factors, such as indoleamine 2,3-deoxygenase (IDO), a link of tumor suppressor gene loss to PD-L1 expression, and therapy-induced resistance. Therapy-induced resistance has been described as cases where patients relapse after having an initial response to immunotherapy, likely as a result of isolated or newly developed resistant tumor clones.^6,7 These additional mechanisms of resistance are the reason for current studies on PD-L1 inhibitors (e.g., atezolizumab, avelumab, and durvalumab) as well as combination studies with IDO inhibitors (e.g., indoximod and epacadostat). As we discover more about pathways of resistance, combination therapy may hold promise for synergy to further improve immune function against cancer. 

Data that currently exist on immunoresistance, especially in humans, are limited. However, several theories have been developed from data on the extensive number of patients who experience little to no benefit or have relapsed disease with immunotherapy. At this point, we are unable to detect which patients may have a durable response and which will have no response. As immunotherapy continues to be studied and approved for various cancer types, more patients will experience disease relapse after an initial response. This will provide a larger sample size to further evaluate immunoresistance by evaluating differences between baseline and relapse tumor DNA. It is important therefore that studies continue to compare biopsies to discover treatment options that will prevent or limit immunoresistance. 

References

1. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006-2017. 

2. Ribas A, Hamid O, Daud A, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315(15):1600-1609. 

3. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375(9):819-829.

4. Hicklin DJ, Wang Z, Arienti F, Rivoltini L, Parmiani G, Ferrone S. Beta2-microglobulin mutations, HLA class I antigen loss, and tumor progression in melanoma. J Clin Invest. 1998;101(12):2720-2729.

5. Restifo NP, Marincola FM, Kawakami Y, Taubenberger J, Yannelli JR, Rosenberg SA. Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J Natl Cancer Inst. 1996;88(2):100-108.

6. Johnson TS, Munn DH. Host indoleamine 2,3-dioxygenase: contribution to systemic acquired tumor tolerance. Immunol Invest. 2012;41(6-7):765-797.

7. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer. 2014;2:3.