Adherence to and Persistence with Oral Anticancer Therapy

Oncology nurses have long prided themselves on their ability to develop trusting relationships with patients and to teach them, as well as their family members, effective self-care so that patients are able to minimize toxicities and adhere to their anticancer therapies. Nurses know there is a narrow therapeutic window with anticancer drugs; thus; side effects must be tolerated in cancer therapy that usually are not tolerated with general medication therapy, such as nausea, vomiting, and diarrhea, as well as side effects that present perhaps life-threatening risks, such as infection and bleeding with bone marrow suppression. However, because many of the side effects occur days from the actual drug administration, nurses have become expert at teaching patients the requisite self-care strategies to safely minimize or recover from side effects. Oncology nurses are challenged with ensuring that their patients and families receive adequate teaching to enable self-care and to minimize toxicities by early reporting and adhering to recommended interventions.

Infusion nurses have time prior to drug administration to assess tolerance of prior treatment, the effectiveness of the symptom management plan, and selfcare ability. While administering treatment, they can further reinforce teaching as well as attend to other tasks, such as triaging patient phone calls to the clinic. During the same visit, nurses can discuss revisions as needed with the physician or midlevel practitioner and revise the plan as needed. This time spent with the patient and family is very important in developing a trusting relationship that is fostered with each visit and telephone call to the clinic. Oral therapies offer a slightly different challenge in that often the treatment nurses do not have an opportunity to meet, let alone develop a trust relationship with patients.

Oral therapies approved for anticancer therapy are increasing in number, and as we have seen, there are many signaling pathways that require blockade; thus, the future may hold “targeted therapy cocktails” that most likely will be oral. As more and more anticancer drugs become oral, the oncology nurse is often left in the infusion room. Because patients receiving only oral antineoplastic therapy are seen by the prescribing physician, nurses may find themselves interfacing with the patient only when they are called in for symptom management. This leaves a large gap in nursing care, and many opportunities to improve patient adherence (following exactly the prescribed instructions) and persistence (ability to continue taking the medication for a long period after the drug is started) for anticancer drug therapy are lost.^{6 8} Ideally, the patient would meet the oncology staff nurse, receive teaching about the oral drug, establish a beginning trust relationship, and then develop an ongoing relationship with the nurse over the course of the oral therapy. Targeted therapies will continue to be prescribed as long as the patient is deriving benefit, which may be a number of years.

It is becoming increasingly clear that adherence to oral therapies is challenging, as is persistence with oral anticancer treatment, as evidenced by failure of patients to take their ordered oral medications exactly as prescribed for as long as it is prescribed.⁹ Thus, nonadherence and inability to persist with treatment is a very important challenge. It results in ineffective treatment, increased costs (including more physician visits and higher hospitalization rates),¹⁰ and is the single most important modifiable factor that compromises treatment outcomes.¹¹

Barriers to Adherence and Persistence

The continued development of oral anticancer drugs, including such agents as multitargeted tyrosine kinases, is two part. On one hand, there is the cost of therapy and reimbursement requirements from Medicare, coupled with the fact that for those who are not cured by cancer therapy, the goal becomes to treat cancer as a chronic illness, which may last for a number of years. On the other hand, patient preference must be considered.¹² While it is recognized that patients with chronic, nonmalignant health problems may not take their medication as prescribed (e.g., the antihypertensive patient who feels well and therefore stops medication), it is a surprise that oncology patients may not adhere or persist in their recommended therapy. For example, one study showed that 15.1% of women who received tamoxifen as part of adjuvant breast cancer treatment chose to stop the tamoxifen before the treatment ended, compared to 26.7% of high-risk women who stopped therapy while taking tamoxifen to prevent breast cancer.¹³ Lash et al. found that 31% of women taking tamoxifen for a prescribed 5-year course had already stopped the drug by the 5-year mark, and that this correlated with the patient's belief about the risk–benefit relationship.¹⁴ This adherence is difficult to measure and ranges from patient self-report to pill counts to drug testing of urine (or principal excretion route). It is possible that when patients know their provider is going to measure their pill count, they are more likely to adhere to the prescribed regimen, called the Hawthorne effect.^{9 15} Specifically included are cost, toxicity, ability to manage or prevent side effects, and personal factors such as ability to remember, belief in therapy, and cultural beliefs.

Reasons for patient preference of oral chemotherapy center around convenience, as the patient can self-administer the dose at home without having the inconvenience or expense of coming to the clinic—aside from scheduled visits. Often the patient believes that oral chemotherapy is less “severe,” with less severe side effects than IV chemotherapy.^{12 16} Conversely, patients may hold a cultural belief that only parenteral drugs will work, and though they may agree with the physician who prescribes the medication to avoid insulting the provider, at home they may become nonadherent.¹⁷

Moore uses the Health Belief Model to better understand patients' motivation to adhere and persist with recommended treatment, which underscores again the

need to assess each patient individually and to modify the teaching plan to meet each individual's needs.¹⁸ Central to this model are (1) the individual's own evaluation of his or her health, such as disease severity and perceived vulnerability to the cancer; (2) individual's risk–benefit assessment of the value and need for adherence to the prescribed therapy; and (3) an internal or external stimulus or “cue to action,” which prompts the individual to take the medicine.¹⁹

Cancer is in general a disease of aging, and 77% of all cancers develop in patients aged 55 years and older.²⁰ In fact, the risk of developing invasive cancer is roughly 1 in 11 (8.44%) in men and 1 in 12 (8.97%) for Americans 40–59 years old, compared to 1 in 6 (15.7%) for men and 1 in 10 (10.23%) for men and women aged 60–69 years, and 1 in 3 (37.7%) and 1 in 4 (26.17%) for men and women, respectively, aged 70 years and older.²¹ Along with age-related physiological changes in the ability to see, hear, and understand that affect a person's ability to carry out self-administration and care instructions, aging brings with it physiological variables that affect drug absorption, together with the risk of drug interactions and the risk of polypharmacy.

Targeted agents are combined with chemotherapy, and the self-administration regimen may be complex based on the different drug bioavailabilities when taken with food. For example, lapatinib is approved by the Food and Drug Administration to be taken with capecitabine. The lapatinib is given twice daily without food (e.g., 2 hours before or after a meal), and the capecitabine is given twice daily, 12 hours apart, within 30 minutes of a meal. In addition, the drugs have a different side effect profile, and while not generally life-threatening, they may pose serious challenges to the patient in terms of continuing therapy (persistence), with effects such as hair and skin changes from epidermal growth factor receptor (EGFR) inhibition and hand–foot reactions from the multitargeted agent sorafenib.

Cost, especially for the elderly with fixed incomes, may be a significant barrier, as is navigating the financial form challenges. The nurse should ensure that there is assistance, either by the nurse, pharmacist, or other member of the team knowledgeable about pharmaceutical drug programs, state and local aid, and other possible supports.

Another issue that may engender nonadherence is lack of understanding about drug cautions and fear of the drug. It is important to teach the patient in a supportive way to wash hands and wear gloves if handling the oral drug, but if possible to pop the drug out of the blister pack.²² However, some drugs come in bottles, and for patients with limited dexterity, it may not be possible not to touch the pill. In addition, patients and families must be taught not to let a pregnant family member touch the drug and that any unused medicine must be returned to the pharmacy for disposal, not put down the toilet. Chan et al. did a cross-sectional survey of patients in Singapore in a single center of 126 patients receiving oral anticancer therapy.²³ They found that although 94% of patients

stated they were adherent to therapy, 40% said they habitually washed their hands after administering the drug but only 1% used gloves.

The nurse assesses the patient for adherence and persistence at each interaction. Sometimes patients takes too much of the oral drug because they think if “a little is good, more is better.” Conversely, patients may try to stretch the pills out if they are costly.¹⁵ Predictors of nonadherence include the following⁹:

• Pill counts at the visit showing more or less than what should remain
• Complex treatment regimens
• Cognitive impairment, depression, or other emotional or psychological issues
• Treatment of asymptomatic disease
• Inadequate follow-up or discharge planning
• Poor patient–provider relationships
• Missed appointments
• Expensive drugs that have limited drug coverage

In summary, barriers to adherence and ability to persist with treatment can be categorized into individual patient behaviors, including cultural beliefs, drug regimen, and problems within the healthcare system^{10 24}:

• Individual patient behaviors: Control issues, culture, health beliefs not supported by adherence, poor or inadequate social support system, denial, depression and other mental illnesses, conflicting responsibilities (e.g., self vs. family), language or cultural differences between provider and patient
• Drug regimen: Complex schedule, change in schedule/routine required
• System factors: Lack of medical support or lack of continuity of care, poor patient education and awareness about disease and treatment, lack of awareness and recognition of the problem of nonadherence by healthcare providers, poor communication/interpersonal relationship between patient and healthcare providers, high cost of medications

Developing Successful Strategies to Support Adherence and Persistence with Oral Anticancer Therapy

Nurses need the time and opportunity to assess patients' ability to self-care and their need for additional support, and to teach patients and their families drugspecific information about side effects and self-administration schedule, to answer questions, and to provide follow-up to assess adherence, problems, and tolerance of the regimen. Nurses must know about the many different drug side effects, prevention strategies to teach the patient, and management priorities. Because it is difficult for the nurse to cover all the aspects of teaching in a short

time, some educational resources have suggested checklists. Projects in Knowledge recommends the following checklist to help nurses organize their patient teaching about targeted therapy²⁵:

• At the start of therapy, discuss expected benefits of therapy, drug dosing and administration, what to do if a dose is missed, and how to store the oral medication.
• Discuss drug side effects—what are common, what are uncommon and should be reported right away?
• Discuss potential barriers to adherence, such as lack of motivation, sideeffect management, and drug cost; provide resources for payment assistance as needed.
• Help patients create strategies to keep track of the medication and to prompt self-administration, such as a pill sorter with or without an electronic monitor, medication planner or calendar, or a timer.
• Assess whether the patient is taking any other prescription, over-thecounter, herbal or complementary medicines, such as St. John's wort, that should be stopped. Teach the patient to report any new medications they want to take BEFORE starting them.
• Discuss the need for dietary modifications, such as avoidance of grapefruit and grapefruit juice if taking drugs that are metabolized by the CYP3A4 microenzyme system.
• Teach women of childbearing age to use effective contraception to avoid pregnancy and to not breastfeed while receiving the drug; teach male patients receiving the epigenetic drugs to use effective contraception while receiving the drug.
• At follow-up visits, assess adherence to the oral regimen and any factors that interfered with adherence; offer alternatives to overcome the barrier.
• Ask if patient experienced side effects and, if so, how they were managed. Offer suggestions to improve management if needed, and answer any questions.

As discussed, many of the targeted therapy side effects are different from those caused by chemotherapy. While nurses are expert in managing diarrhea, they must learn about and become proficient in managing hypertension, EGFR-rash, and hand–foot skin reactions. In addition, they need to teach patients about potentially serious events such as bleeding and cardiac and lung toxicities. The Oncology Nursing Society has evidence-based recommendations for many symptoms such as the management of fatigue, stomatitis, and diarrhea. It is important for nurses to write specific schedules for self-administration of the drugs; for example, erlotinib should be taken at least 1 hour before or at least 2 hours after food, as it significantly increases the drug's bioavailability when the drug is taken with food. If the patient calls with increased toxicity such as diarrhea, the nurse

should first ask how the patient is taking the medication (e.g., with food?). Lapatinib is given at a dose of 5 tablets daily, at least 1 hour before or 1 hour after meals, while capecitabine, which is prescribed along with lapatinib, is given twice daily 12 hours apart, within 30 minutes of a meal. Imatinib is given daily for most indications with water and a meal. Sorafenib is given twice daily, at least 1 hour before or 2 hours following food. Sunitinib is given daily with or without food for 4 weeks; the patient is then off therapy for 2 weeks, and the cycle is repeated. Thus, it is clear that a written calendar with boxes to check after the drug is given may be helpful.

Hartigan recommends that each treatment plan be individualized to the patient based on the patient's ability to learn; perceived barriers such as impaired vision, hearing, or ability to understand the nurse's instruction; and motivation.⁷ Winklejohn suggests developing standardized written prescriptions, encouraging the use of patient diaries, using medication calendars with check-off boxes, and using drug-specific patient teaching sheets.⁶ Many nurses suggest pillboxes, and while these in the past have been offered by pharmaceutical companies, the growing industry-wide attempt to limit vendor influence on prescribing practices has limited the ability of nurses to use these patient educational materials or boxes.

Partridge et al. summarize practical ways to enhance adherence to oral antineoplastic regimens¹⁰:

• Improve patient–provider communication (e.g., implement skills training for providers, use checklists for dimensions of dialogue, emphasize disease management, not cure, tailor communication to each patient, keep message simple, explain treatment plan carefully, use existing technologies that are appropriate for the patient/family, enlist help of primary care provider, develop reinforcement strategies, consider a patient newsletter addressing adherence and patient issues).
• Increase patient educational opportunities (e.g., waiting room resources, classes on oral therapy, patient support groups).
• Enhance patient role in adherence (e.g., give expectations and medication side effects as well as helpful tips on self-care and adherence, encourage open communication, and reinforce mechanism to report side effects and difficulty getting medicines).

The 2009 American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards, a consensus guideline for outpatient administration of chemotherapy (defined to include targeted agents), recommends the following²⁶:

• Practice site should maintain and use standardized regimen-level preprinted forms or computer-generated forms for chemotherapy prescription writing.
• Oral chemotherapy orders should be time-limited and may not be prewritten for more than the written chemotherapy plan allows.
• Prior to starting chemotherapy, the patient should be given written documentation, including at a minimum information about diagnosis, goals of therapy, planned duration of chemotherapy drugs and schedule, information on potential short- and long-term side effects, emergency contact information, and plan for monitoring and follow-up.
• Written or electronic patient educational materials about oral chemotherapy should be provided before or at the time of the prescription (preparation, administration, and disposal); educational plan includes family, caregivers, and others based on the patient's ability to assume responsibility for managing self-care.
• Educational materials for patient and caregiver should be appropriate for the patient's reading level and literacy.
• The frequency of office visits and monitoring is appropriate to the agent and is defined in the treatment plan.
• Practice site should have a procedure for documentation and follow-up of patients who miss office visits or treatments.
• Toxicity assessment documentation should be available for planning subsequent treatment cycles.

As our population increases, it is likely that more multicultural patients with cancer will be treated. Avery recommends the following to maximize adherence¹⁷:

• Use an objective measurement of adherence, such as a patient's refill history or pill count.
• Ask patients to bring in all their medications at each visit (even if it is not their own prescribed medicine).
• Ask open-ended questions rather than yes or no questions, and use a trained interpreter when language is a barrier.
• Be proactive to get to know patients and to build a trusting relationship with them.
• Take time to explain the diagnosis, cause, and treatment regimen clearly. State the realistic expectations of side effects, dietary changes if any, and support to help patients minimize side effects and promote selfcare. Elicit the patient's understanding of the disease, drug, and potential side effects.
• Explain the rationale for each medication, and label the drug with the corresponding condition or symptoms.
• Ask questions about intake of traditional medicines, herbs, fasting periods, etc., and any other cultural factors that might influence adherence.
• Providing pictures and written information in the patient's language as well as English can be helpful. Many patients have a family member who can read English, while others can understand only very simple elements, such as numbers.
• Avoid complicated medication regimens if possible, and simplify the regimen as much as possible so the patient can comply.
• Emphasize the importance of continuing the medication even if the patient feels well.
• Suggest reminder tools such as Medisets, medication organizers, or alarm systems.
• Balance an authoritative role over the patient by being decisive, but allow for safe treatment changes based on patient's self-perceived needs.
• Have the patient tell you at the end of the appointment what you told him or her so you can assess understanding and recall.

Barefoot et al. have developed and implemented a system intended to maximize the patient's success with adherence and persistence.²⁷ The system proceeds as follows:

1. The physician tells the nurse that an oral anticancer agent is being prescribed.
2. The physician gets the patient's informed consent using the chemotherapy/biotherapy informed consent.
3. Orders are written on an oral anticancer order sheet, which is sent to pharmacy.
4. The pharmacy screens for interactions with the patient's current medications.
5. The patient is given an appointment for education teaching about the medication as well as safe handling, by an advanced practice nurse.
6. Pre-authorization is obtained as needed or the patient is referred for an assistance program, and pre-authorization for monitoring of laboratory values as needed is also obtained.
7. Patient is given the prescription as well as information about the drug, which is documented in the teaching note.
8. The patient is given a calendar to mark off the doses as they are taken, along with a pillbox and printed material during the educational appointment.
9. The patient's medications are added to the medication reconciliation sheet in the patient's chart.
10. The patient is asked to bring in all prescription bottles at each visit.
11. A note is placed in the follow-up appointment screen (for oral therapy) to remind secretaries that when they call the patients to confirm their next appointment, they should remind them to bring their prescription bottles.

In summary, nurses have much power to help patients and their families value and participate in adherence and persistence of treatment. Nurses assess barriers, and individually provide their patients with strategies that minimize risk of nonadherence and treatment discontinuance (nonpersistence). In addition, the

nurse acts as a catalyst to change many of the institutional or health system barriers to provide effective communication and patient teaching, to reinforce learning, and to establish a trust relationship with their patients and families.