The advent of novel agents, many with specific molecular and genetic targets to treat hematologic malignancies, has revolutionized the management of these cancers and resulted in better disease control and unprecedented survival rates. This has resulted in a paradigm shift toward a chronic care model for many hematologic cancers that traditionally were not regarded as chronic conditions. Several of these approved novel agents are targeted oral anticancer medications that offer many potential advantages over traditional intravenously administered drugs, such as convenient home-based treatment, flexibility, avoidance of IV infusions, providing a sense of control over treatment, and resulting in minimal disruption of activities of daily living. Evidence also suggests that many oncology patients prefer oral treatment to IV.1 However, the growing use of oral medications has significant implications for the practical management of the hematologic malignancy subtypes for which they are indicated. They are redefining the oncology cancer care models of patient care, including the roles and responsibilities of providers and patients. Importantly, the use of oral medications has shifted the burden of responsibility of medication administration from the provider to the patient and caregiver. Whereas the in-clinic IV administration of medication provides direct control and assures the provider of medication storage, delivery, and schedule, the use of oral medications creates new challenges for healthcare professionals (HCPs) in terms of maintaining adherence to treatment as prescribed and brings into focus the need for patient education, monitoring, and support.
In the scope of their responsibilities, oncology nurse navigators (ONNs) can potentially play an important role in ensuring patient adherence to oral therapies. The Academy of Oncology Nurse & Patient Navigators defines a nurse navigator as “a clinically trained individual responsible to identify and address barriers to timely and appropriate cancer treatment. They guide the patient through the cancer care continuum from diagnosis through survivorship.”2 Oncology navigation is increasingly being used in healthcare delivery models to enhance patient-centered care and allow for a central point of contact within a patient’s multidisciplinary healthcare team to ensure follow-through of treatment plans.2
The role of ONNs in supporting medication adherence is indispensable in the context of hematologic malignancies, which are a heterogeneous and broad group of cancers that affect blood, bone marrow, and lymph nodes. Hematologic malignancies account for around 10% of all newly diagnosed cancer cases in the United States, and together account for around 9% of annual cancer-related deaths.3 Main subcategories of hematologic malignancies include leukemias, lymphomas, and multiple myeloma (MM).4 This diverse group of cancers is associated with different incidences, disease courses, prognoses, and survival.5 Certain lymphoma and leukemia subtypes are slow growing and exhibit an indolent disease course, such as chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), and follicular cell lymphoma. However, as mentioned earlier, treatment advances for many other subtypes have altered the disease courses such that they are now regarded as chronic conditions, requiring extended and continued treatment and support for several years. A multitude of oral medications are available for many hematologic conditions that require prolonged care, bringing discussions of medical adherence to the forefront. Given that oncology nurses and nurse navigators are an integral part of the patient care team and are involved in many aspects of the cancer care continuum, this article discusses their role in maintaining long-term treatment adherence in hematologic malignancies.
Ensuring Patient Adherence to Prescribed Treatments
Adherence to a medication regimen is generally defined as the extent to which patients take medications as prescribed by their healthcare providers.6 Adherence rates are typically measured as the percentage of the prescribed doses of the medication actually taken by the patient over a specified period.
Rates of Adherence
In the literature, rates of adherence to oral cancer therapies vary substantially. This wide variation may be attributed to several factors influencing study outcomes, including differences in cancer subtype, medication type, follow-up period, assessment measure, lack of standardization in defining optimal adherence, and poor methodological quality of studies.7 This systematic review of adherence to oral drugs from about 51 studies also indicated that poor adherence to oral antineoplastic therapy was associated with longer duration of therapy.7 In hematologic malignancies, a pilot study of 90 patients with many cancers, including CML, showed that perfect adherence was achieved by only one-quarter of the patients. Further, only 65% of patients with CML were adherent to oral chemotherapy when using more advanced adherence reminder tools, such as electronic pill cap technology.8 A pharmacy record analysis of 4043 patients prescribed imatinib showed that 30% of patients interrupted therapy for at least 30 consecutive days in the first year, and only 41% of the total patients were more than 90% adherent.9
Adherence Linked to Treatment Outcomes
Nonadherence can have serious ramifications for patients and can negatively impact overall treatment outcomes. Nonadherence has been associated with adverse effects, such as disease progression, additional physician visits, preventable hospitalizations, and increased mortality.6 In the phase 3 RESONATE trial of the Bruton’s tyrosine kinase inhibitor (TKI) ibrutinib administered once daily in patients with CLL, patients missing ≥8 consecutive days of ibrutinib had a shorter median progression-free survival versus those missing <8 days (10.9 months vs not reached).10 Nonadherence to medication regimen was found to be associated with a 2-fold higher incidence of preventable medication-related hospital admissions.11
Conversely, several studies have found that adherence to oral medication is directly linked to better treatment outcomes. In CML, strong evidence indicates that adherence to the TKI imatinib therapy is a critical factor for achieving deep molecular responses that correlate with treatment-free remission.9,12,13 In one study, adherence to imatinib therapy (≤90% or >90%) in patients with CML was associated with higher major molecular response in BCR-ABL1 transcripts (28.4% vs 94.5%; P <.001) and complete molecular response (0% vs 43.8%; P = .002).12 Other predictors of better adherence include improved symptom distress, mood, quality of life, satisfaction with providers and treatment, and perceived burden to others.12
Barriers to Adherence
Nonadherence is a multifaceted issue. Several barriers to medication adherence are recognized, including patient, clinician, treatment, and system factors, as discussed below. Patient-related factors may include health literacy in terms of lack of understanding of the disease and risks of medication nonadherence, incorrect perception of being cured; lack of belief in treatment benefits, reluctance to change behaviors, age/sex, forgetfulness, comorbid conditions, and polypharmacy (Table 1). In a study of pharmacy records, adherence significantly improved with age until age 51 years and then declined rapidly, decreased with polypharmacy, and was lower in women and patients with more cancer complications. This is significant because many patients with hematologic malignancies require multiple medications concomitantly.9 Another patient-driven survey-based study assessed the extent of suboptimal adherence and investigated motivations and behavioral patterns of adherence in 2546 patients with CML from 63 countries.14 Not surprisingly, the study found that contributors to adherence were multifactorial. Older age, male sex, and living alone all arose as independent contributors to nonadherence.14
Treatment-related factors such as medication side effects, complexity of treatment schedules, and drug-drug interactions can result in medication nonadherence.15 The complexity of a treatment regimen, such as a complicated dosing schedule, might be challenging for the patient and negatively impact their ability to follow a regimen. A large systematic review of 76 trials found that adherence was inversely proportional to frequency of dose, with patients taking medication 4 times daily achieving average adherence rates of only about 50% (range, 31%-71%). On the other hand, when the frequency of the drugs is not daily, it might also pose difficulties in terms of remembering to take them per the prescribed schedule. For example, the histone deacetylase inhibitor panobinostat needs to be taken 3 times a week, whereas the proteasome inhibitor ixazomib is taken once per week. Although oral drugs such as lenalidomide, which is a mainstay of treatment in the management of MM, follow a relatively simple daily regimen for 2 or 3 weeks followed by a week of rest, it is often given in combination with oral steroids and other active agents such as ixazomib; in such instances, complicated dosing schedules might become challenging for patients to follow, particularly if cognitive deficits are present. Polypharmacy is also an underappreciated barrier to oral medication adherence. With polypharmacy, the risk of drug-drug interactions must be assessed and adequately addressed. For example, drug-drug interactions are known to occur between the CML TKI imatinib and the antimycobacterial rifampin, as well as between the TKI gefitinib and anticoagulants.16,17
An important determinant of medication adherence is presence of side effects and their inadequate management; ongoing side effects may be a source of frustration for patients, prompting them to diverge from their prescribed dosage schedule or discontinue altogether without notifying their treatment team. In a large patient survey study, patients with no side effects were more adherent than patients who experience side effects.14 Importantly, patients who perceive their side effects to be well managed were more adherent than those who did not think their side effects were well managed, underscoring the importance of toxicity management for better medication adherence.14 Moreover, some patients might have the perception that oral pills are associated with fewer side effects and better quality of life compared with IV therapy, thereby potentially causing them to underestimate or underreport adverse events when they actually do occur. Therefore, it is important that ONNs educate patients and set expectations about potential side effects of oral medications.1
Socioeconomic factors, such as financial toxicity, limited access to healthcare facilities and/or pharmacy, social lifestyle, lack of family or support network, and inadequate supervision, might also be strong determinants of medication adherence.15 Financial burden may include lack of health insurance or inadequate insurance coverage resulting in high out-of-pocket costs, which may prompt the patient to either stop the medication altogether, skip doses, or even split doses to make the medication last longer. Analysis of 2 large retrospective claims databases that identified CML patients who received second-line dasatinib or nilotinib showed that dasatinib patients incurred $8828 more in total medical service costs, which correlated with lower adherence.18
Given these various barriers to medication adherence, it is imperative that HCPs take timely and adequate measures to educate and address patient and treatment-related barriers. However, poor patient-provider communication, lack of positive reinforcement from HCPs, lack of adequate education on medication regimen or importance of adherence, and infrequent follow-up have been cited as important contributors to medication nonadherence. Therefore, it is critical that HCPs identify individual barriers to and facilitators of medical adherence to oral drugs in patients with hematologic malignancies requiring long-term management to improve patient outcomes. Furthermore, this significantly underscores the contribution nurse navigators can play in addressing barriers and limitations to patient adherence. In particular, from a clinical practice perspective, oncology nurses and nurse navigators must take the responsibility of identifying and addressing barriers to medication adherence given their frontline functions in side effect management, procurement, care coordination, patient education, and follow-up care.2 Attesting to the validity of the role of nurses, nurse-led interventions have been shown to positively impact medication adherence.19,20 A medication adherence survey administered to newly diagnosed or preexisting CML or MM patients at 2 outpatient oncology clinics indicated an improvement in treatment beliefs and medication-taking behavior following institution of adherence-promoting strategies.20
Interventional Strategies to Improve Medication Adherence
Intervention to improve medication adherence demands a collaborative approach to decision-making between the patient and prescriber in terms of medication choice, dosing, and frequency of administration. Given the multidisciplinary nature of a hematologic malignancy management and treatment team, however, the ONN’s longitudinal role in following the patient throughout the treatment continuum can positively contribute to their medication adherence. As such, the ONN may be the first individual a patient communicates with regarding their treatment (eg, planning, scheduling, concerns, questions, adverse effects, etc). Therefore, they are often in a key position to influence outcomes and successful therapy.
The shared decision-making (SDM) model is recommended by both the Institute of Medicine and the US Preventive Services Task Force as the best practice to improve medication adherence.21 The SDM framework empowers patients to be engaged in their own care; it allows the patients to express their preferences and goals and collaborate with the provider in making the final treatment decision. In a recent systematic review, patients indicated that they preferred the SDM, with such engagements leading to positive health outcomes, including improved self-reported health status, self-management behaviors, emotional health, satisfaction with care, and adherence to treatment plans.22,23 SDM entails that a patient understands the treatment options available to them in order to make informed decisions. ONNs educate their patients on cancer stage/status, treatment plan, adverse effects of treatment, and need for treatment, as well as address remaining concerns or questions. They serve to encourage complete and thorough patient comprehension regarding their care.2 Thus, through education and a strong rapport established between patients and their nurse navigators, communication to successfully contribute to an SDM model—and ultimately increase the chance of patient adherence—is more achievable.
Models of adherence interventions typically contain several elements, including patient education, side effect management, behavioral interventions, patient communication, simplifying medication regimens, and applying reminder cues.6,24 It is important to understand that an individualized approach must be adopted by identifying individual barriers and tailoring adherence interventions to individual needs. A Cochrane review showed that successful adherence interventions for long-term care included the following elements: education, reminders, self-monitoring, reinforcement, counseling, family/caregiver therapy, psychological therapy, crisis intervention, manual telephone follow-up, and supportive care.25 Importantly, nurse navigators are in a position to contribute to all of the aforementioned interventions. As a patient’s main point of contact on their cancer healthcare team, ONNs can identify and address patient barriers to treatment, and, if necessary, refer a patient to experts or resources outside of their own scope of practice to positively impact a patient’s adherence (eg, financial advisors, social work support, psychosocial counseling, direct contact with HCP, etc).26
Patient education can positively affect adherence to oral anticancer medication. An interventional study in imatinib-prescribed patients with CML found that patients randomized to a counseling program showed a 93.0% medication adherence compared with 76.2% with patients receiving standard care. Counseling strategies included phone consultations by a nurse, daily text messaging reminders, and written communication by their medical team.27 The education/counseling must be directed toward alleviating patient fears and concerns relating to medication side effects, recognizing early signs of toxicity, proactive prevention with supportive agents, and contacting their HCP in a timely manner. To avoid potential drug-drug interaction, concomitant medications must be reviewed. In addition to in-person instructions provided in the clinic setting, written instructions and information pamphlets must be provided for reference at home. This information packet must also contain the treatment plan that includes the goal of therapy, timing and dosing of therapy, special considerations, and monitoring and follow-up schedule. The HCP or nurse navigator must be in regular contact with the patient during the treatment period to reinforce the importance of medication adherence and identify any barriers. The frequency of monitoring and follow-up strategies, such as office visits, web-based patient portals, and phone-based checkups that are appropriate for the individual and the oral drug prescribed must be determined and defined in the treatment plan.26
Several adherence aids and reminder cues are available to improve adherence outcomes. Reminder triggers include pillboxes, pill diaries, and treatment calendars.28 In addition, reminders set up on the phone or sending text messages based on the dosing schedule and time are commonly strategies that are effective.28 Calendars, checklists, and postcard/e-mail reminders may be used as refill reminders so that patients have an adequate supply of medications.28 The Oncology Nursing Society has developed an oral adherence tool kit that includes several tools, resources, and information on interventional strategies that nurses may employ to promote medication adherence.29
Assessments of medication adherence to oral therapies must be routinely performed to ensure that medications are taken as prescribed. Several strategies for medication adherence assessments are available, which can broadly be classified as direct and indirect methods (Table 2). Direct methods include directly observed therapy, measurement of the level of a drug or its metabolite in blood or urine, and measurement of a biological marker in the blood. Although direct approaches are most accurate, they are expensive and may require additional doctor visits, which may be burdensome to some patients. Indirect methods include patient questionnaires, patient self-reports, pill counts, rates of prescription refills, assessment of patient’s clinical response, electronic medication monitors, measurement of physiologic markers, and patient diaries. The limitations of these methods are that they are subjective and may be susceptible to alteration by patients, inaccurate data entries, recall bias, or error with increased interval between patient visits. Although patient questionnaires and self-reports are simple, inexpensive, and widely used in clinical settings, they may not accurately capture patient adherence because of its subjective nature, and it is easily distortable. Pill counts do not account for adherence to dosing schedule and are amenable to manipulation.30 Incorporation of a microelectronic monitoring system (MEMS) into pill containers allows tracking of the opening of pill container but cannot be correlated with pill ingestion. Evidence of a clinical response can confirm patient adherence to oral medication but can be affected by other factors. Assessing prescription filling and insurance records is considered to provide the most accurate estimate of actual medication use over a period of time; however, it may not accurately translate to pill consumption or to determine whether the patient is taking the medication as prescribed. Comparison of several of these medication adherence assessment methods found that medication adherence rates by self-report and pill count were higher than other methods, which might not necessarily correlate with actual medication adherence; the best correlation was noted between physiological assessments by checking plasma marker levels and electronic methods such as MEMS.31 Although the aforementioned strategies all have limitations, they contribute positively to improved medication adherence when tailored to the patient’s individual needs.
Optimizing adherence to oral medications is essential to maximize treatment effectiveness, avoid medication changes, prevent unnecessary hospitalizations, reduce healthcare costs, and improve overall patient outcomes in patients with chronic hematologic malignancies. Toward this end, a patient-centered model of care is needed that incorporates patient-provider SDM while integrating other essential elements, such as patient education, side effect management, behavioral interventions, patient communication, simplifying medication regimens, and applying reminder cues. The nurse navigation approach to patient-centered care, if implemented in a medical practice, has the potential to greatly facilitate these efforts and minimize barriers to adherence.
- Eek D, Krohe M, Mazar I, et al. Patient-reported preferences for oral versus intravenous administration for the treatment of cancer: a review of the literature. Patient Prefer Adherence. 2016;10:1609-1621.
- Academy of Oncology Nurse & Patient Navigators. https://aonnonline.org. 20119. Accessed October 9, 2019.
- Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts. www.seer.cancer.gov. 2019. Accessed October 9, 2019.
- National Cancer Institute. Dictionary of Cancer Terms. Bethesda, MD: National Cancer Institute. www.cancer.gov/publications/dictionaries/cancer-terms. 2019. Accessed October 9, 2019.
- National Comprehensive Cancer Network. Guidelines for treatment of cancer by site. www.nccn.org/professionals/physician_gls/default.aspx#site. 2019. Accessed October 9, 2019.
- Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005; 353:487-497.
- Greer JA, Amoyal N, Nisotel L, et al. A systematic review of adherence to oral antineoplastic therapies. Oncologist. 2016;21:354-376.
- Jacobs JM, Pensak NA, Sporn NJ, et al. Treatment satisfaction and adherence to oral chemotherapy in patients with cancer. J Oncol Pract. 2017;13:e474-e485.
- Tsang J, Rudychev I, Pescatore SL. Prescription compliance and persistency in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST) patients (pts) on imatinib (IM). J Clin Oncol. 2006;24. Abstract 6119.
- Barr PM, Brown JR, Hillmen P, et al. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood. 2017;129:2612-2615.
- Leendertse AJ, Egberts AC, Stoker LJ, et al. Frequency of and risk factors for preventable medication-related hospital admissions in the Netherlands. Arch Intern Med. 2008;168:1890-1896.
- Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28:2381-2388.
- Noens L, Hensen M, Kucmin-Bemelmans I, et al. Measurement of adherence to BCR-ABL inhibitor therapy in chronic myeloid leukemia: current situation and future challenges. Haematologica. 2014;99:437-447.
- Geissler J, Sharf G, Bombaci F, et al. Factors influencing adherence in CML and ways to improvement: results of a patient-driven survey of 2546 patients in 63 countries. J Cancer Res Clin Oncol. 2017;143:1167-1176.
- Cheung WY. Difficult to swallow: issues affecting optimal adherence to oral anticancer agents. Am Soc Clin Oncol Educ Book. 2013:265-270.
- Bolton AE, Peng B, Hubert M, et al. Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol. 2004;53:102-106.
- Onada S, Mitsufuji H, Yanase N, et al. Drug interaction between gefitinib and warfarin. Jpn J Clin Oncol. 2005;35:478-482.
- Wu EQ, Guerin A, Yu AP, et al. Retrospective real-world comparison of medical visits, costs, and adherence between nilotinib and dasatinib in chronic myeloid leukemia. Curr Med Res Opin. 2010;26:2861-2869.
- Schneider SM, Adams DB, Gosselin T. A tailored nurse coaching intervention for oral chemotherapy adherence. J Adv Pract Oncol. 2014;5:163-172.
- Lea SC, Bohra S, Moore T, et al. Exploring behaviors, treatment beliefs, and barriers to oral chemotherapy adherence among adult leukemia patients in a rural outpatient setting. BMC Res Notes. 2018;11:843.
- Berwick DM. A user’s manual for the IOM’s ‘Quality Chasm’ report. Health Aff (Millwood). 2002;21:80-90.
- Chewning B, Bylund CL, Shah B, et al. Patient preferences for shared decisions: a systematic review. Patient Educ Couns. 2012;86:9-18.
- Hibbard JH, Mahoney ER, Stock R, Tusler M. Do increases in patient activation result in improved self-management behaviors? Health Serv Res. 2007;42:1443-1463.
- Accordino MK, Hershman DL. Disparities and challenges in adherence to oral antineoplastic agents. Am Soc Clin Oncol Educ Book. 2013:271-276.
- Haynes RB, Ackloo E, Sahota N, et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev. 2008:CD000011.
- Anderson MK, Reff MJ, McMahon RS, Walters DR. The role of the oral oncology nurse navigator. Oncology Issues. September-October 2017:25-30.
- Moon JH, Sohn SK, Kim SN, et al. Patient counseling program to improve the compliance to imatinib in chronic myeloid leukemia patients. Med Oncol. 2012;29:1179-1185.
- Schneider SM, Hess K, Gosselin T. Interventions to promote adherence with oral agents. Semin Oncol Nurs. 2011;27:133-141.
- Oncology Nursing Society. Oral Adherence Toolkit. www.ons.org/sites/default/files/ONS_Toolkit_ONLINE.pdf. 2016. Accessed October 14, 2019.
- Partridge AH, Avorn J, Wang PS, Winer EP. Adherence to therapy with oral antineoplastic agents. J Natl Cancer Inst. 2002;94:652-661.
- Velligan DI, Wang M, Diamond P, et al. Relationships among subjective and objective measures of adherence to oral antipsychotic medications. Psychiatr Serv. 2007;58:1187-1192.