Arthur P. Staddon, MD
Joan Karnell Cancer Center, University of Pennsylvania School of Medicine, and Department of Hematology and Oncology, Pennsylvania Hospital, Philadelphia, PA
Manuscript received December 22, 2010; accepted June 10, 2011.
Correspondence to: Arthur P. Staddon, MD, Department of Hematology and Oncology, Pennsylvania Hospital of the University of Pennsylvania Health System, 230 West Washington Square, Philadelphia, PA 19107; e-mail: ArthurStaddon@pennoncology.com.
Oral anticancer drugs, particularly targeted therapies, are used increasingly to treat many solid malignancies. Adherence to the prescribed regimen is essential to ensuring that patients derive maximal clinical benefit from these
oral agents. However, multiple patient-related, treatment-related, and healthcare-associated factors may adversely impact adherence, thus compromising patient outcome. Reliable methods are not readily available in clinical practice to identify which patients are nonadherent. Therefore, clinicians need to take a proactive approach by assessing their patients’ needs, providing education about what can be expected during the course of oral therapy, monitoring adherence and reinforcing key points at all office visits, and using follow-up phone calls to identify issues that may still have an impact on adherence. By identifying and addressing barriers to adherence, oncologists can help their patients realize the full potential of oral therapy, including the promise of improved clinical outcome and quality of life.
Parenteral cytotoxic chemotherapy has traditionally been the major component of treatment for many solid malignancies—both in the adjuvant/neoadjuvant setting for high-risk localized disease and in the primary treatment for advanced and unresectable disease. Some oral anticancer agents, including tamoxifen, prednisone, and cyclophosphamide, have been used to manage certain malignancies for many years,1 and other oral cytotoxic drugs, such as capecitabine (Xeloda), have recently increased in usage.2,3. However, the advent of targeted therapy with agents that block specific cellular processes thought to be important in cell growth, survival, and metastasis has led to a large increase in the number of oral drugs for cancer.4 With the increased use of oral cancer drugs comes a shift in the treatment paradigm as it relates to patient management, particularly patient adherence to therapy. Examples of such oral targeted agents include the KIT/plateletderived growth factor receptor (PDGFR) tyrosine kinase inhibitors imatinib (Gleevec)5 and sunitinib (Sutent),6 the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib (Tarceva) 7 and gefitinib (Iressa),8 the vascular endothelial growth factor receptor (VEGFR)/PDGFR kinase inhibitor pazopanib (Votrient),9 the multikinase inhibitor sorafenib (Nexavar),10 and the mamma lian target of rapamycin (mTOR) inhibitor everolimus (Afinitor).11
Notably, oral targeted therapy has emerged as a primary treatment of certain solid malignancies, including advanced gastrointestinal stromal tumors (GIST) and metastatic renal cell carcinoma.12 For example, imatinib is now recognized as first-line treatment of advanced GIST, and sunitinib is used in the second-line setting when patients relapse or cannot tolerate imatinib.12 Imatinib is also used in adjuvant therapy following complete surgical resection of localized GIST in patients with an intermediate or high risk of disease recurrence.12,13 Although no oral therapies are currently approved for treatment of bone or soft-tissue sarcomas, several are in clinical trials—the most advanced of which include two placebo-controlled, phase III trials evaluating the mTOR inhibitor ridaforolimus and the tyrosine kinase inhibitor pazopanib. Ridaforolimus is being evaluated as maintenance therapy for patients with favorable responses to chemotherapy, in the Sarcoma Multicenter Clinical Evalua tion of the Efficacy of Ridaforolimus (SUCCEED) trial.14 In the Pazopanib Explored in Soft-Tissue Sarcoma a Phase III (PALETTE) trial, pazopanib is being investigated in patients whose disease has progressed during or following prior therapy.15
Cancer patients generally prefer oral therapy over intravenous (IV) therapy, provided that efficacy is not compromised.1,16,17 Oral therapy offers greater convenience because it eliminates the time constraints imposed by receiving IV therapy at a physician’s office or treatment clinic. 18,19 This benefit may be particularly important for patients who live a significant distance from a treatment center.20 Oral therapy also reduces the discomfort and anxiety of having a venous catheter inserted for each treatment and it is easier in cases where venous access is difficult.20 Clinicians also are generally reported to prefer oral therapy, as it prevents complications such as infections and clotting associated with venous access and infusion pumps.2
The benefits of oral therapy must be balanced against several potential disadvantages, not the least of which is patient adherence to prescribed treatment. Patients receiving IV treatment may see their oncologist at intervals of 1 to 3 weeks, whereas those on oral agents may have less frequent visits. This arrangement limits educational and monitoring opportunities, as well as positive reinforcing interactions between patients and clinicians.22 The positive reinforcement and education provided by oncology nurses during IV treatment sessions are also lost.23 Perhaps most important, however, is that oral therapy requires patient self-medication and depends on the ability of patients to adhere to a prescribed regimen, which may involve daily treatment. More complex regimens may include multiple daily doses, drug holidays, or dosing based on the timing of meals.
Poor patient adherence is a well recognized issue in the treatment of many chronic diseases, including hypertension, diabetes, asthma, and mental illness.24 With oral therapies, long-term treatment is generally necessary to maintain disease control. However, adherence tends to decrease during long-term treatment, and therefore poor adherence may be more problematic during long-term maintenance with a targeted agent than with short-term use of an oral cytotoxic drug (Figure 1).25 The goal of maintaining high-level treatment adherence is to achieve optimal control of disease and to prevent, to the highest extent possible, disease progression.
Treatment adherence with oral anticancer agents
An overview
The terms “adherence” and “compliance” are used to describe the degree or extent to which a patient conforms to day-to-day treatment recommendations, including the timing, dosage, mode of administration, and frequency of the medication(s).26 Adherence is a synonym of compliance and is often perceived to be less judgmental of the patient’s behavior.27 Optimal adherence is achieved when a patient follows the treatment regimen exactly as prescribed (ie, without missing doses or taking extra doses). Therefore, adherence simply reflects the percentage of doses that are taken as prescribed.26
Monitoring treatment adherence in clinical practice is challenging, with all methods having significant limitations.1,27 Patient self-reporting may not accurately reflect treatment-taking behavior, because patients who want to please their clinicians will often overreport actual adherence. Patients completing medication diaries may erroneously fill in doses they failed to take, particularly at times close to scheduled visits. Additionally, these methods may provide unreliable information about the timing of doses, which is also important in ensuring appropriate systemic exposure to oral therapy. Other approaches have been used in clinical studies, including monitoring prescription refills and the microelectronic monitoring system (MEMS), which records each time the cap of the medication bottle is opened. However, opening the bottle does not ensure that the patient has taken the medication.
Therapeutic drug monitoring, measured through assessment of serum or urine drug levels, when available, may help to determine whether a patient has been adherent; however, it provides information for only the brief time leading up to testing and is limited by substantial interpatient variability in pharmacokinetics. Therapeutic drug monitoring also requires additional costs, further limiting its utility in clinical practice.
Adherence and the cancer patient
Cancer patients are generally thought to be highly motivated to follow their prescribed regimen.1,25 However, studies show that adherence with oral anticancer drugs is not optimal and that self-reporting and pill counts may not accurately reflect true patient behavior. Most information about medication adherence in patients with solid tumors comes from studies of tamoxifen in breast cancer.
In a study of a small cohort of breast cancer patients receiving tamoxifen for a mean of 3 months, the average adherence rates based on self-reports and pill counts were 98% (range, 91%–100%) and 92% (range, 74%–109%), respectively, with several patients taking more doses than prescribed. In comparison, MEMS showed an average rate of 69% (range, 33%–94%).28 Similar differences in adherence rates based on self-reports versus prescription refills have been seen with adjuvant tamoxifen and anastrozole. 29 Although self-reported adherence of 100% was claimed for both agents, only 80% and 69% of the women on tamoxifen and anastrozole, respectively, were still classified as adherent after controlling for prescription refills (P < 0.01 and P < 0.01 vs self-report).29 In general, electronic adherence measures, such as MEMS, show higher agreement with refilled pharmacy prescriptions than with patient self-reports.30
Adherence to oral cytotoxic drugs may also not be optimal in cancer patients. Adherence to oral capecitabine was assessed using MEMS in a cohort of 161 elderly women receiving adjuvant therapy for breast cancer. Twenty-four percent of the patients took fewer than 80% of the planned doses.31 Similarly, a nonadherence rate of 43% was reported for 51 breast cancer patients receiving oral cyclophosphamide, with higher nonadherence observed when women were treated in community practice settings than at academic centers.32 To date, assessments of treatment adherence to oral targeted therapies have shown a relatively high proportion of nonadherence in patients with hematologic malignancies (eg, chronic myelocytic leukemia).33 Adherence in patients with solid tumors has not been studied as extensively. Clinicians should suspect poor adherence when patients fail to achieve expected treatment responses within a certain time or when prescriptions are not filled as often as expected.
Impact of poor adherence
Patients with poor adherence may not receive the full benefit of treatment and may consequently experience poor clinical outcomes. Two sample populations illustrate this point—women with breast cancer and patients with advanced GIST. Adjuvant tamoxifen is well recognized to improve survival of women with hormone receptor-positive early- stage breast cancer.34 The impact of tamoxifen adherence on outcome was evaluated in a cohort of 1,633 women who received treatment for a median of 2.4 years.35 Median adherence was 93%; however, 315 women (19%) had adherence rates of less than 80%. In the multivariate analysis, a low adherence rate was independently associated with a higher risk of death. At the median study follow-up, the hazard ratio for mortality with adherence of less than 80% was 1.10 (95% confidence interval: 1.001–1.21; P = 0.046).35
Oral imatinib changed the treatment of advanced GIST, extending median survival to nearly 5 years.5 Poor adherence with daily imatinib leads to low serum drug levels, which in turn has been associated with poor clinical outcomes. Patients with serum imatinib levels less than 1,100 ng/mL—the lowest quartile in a recent analysis—had a median time to disease progression (TTP) of 11.3 months, which was significantly shorter than the TTP of greater than 30 months seen in the other three serum imatinib quartiles.36
Another randomized study compared planned interruption versus continuation of imatinib therapy in patients with advanced GIST.37 Most patients assigned to stop imatinib after achieving objective responses or stable disease on long-term therapy had rapid disease progression. Conversely, most patients who continued imatinib without interruption maintained the clinical benefit. Although treatment interruption was a planned event in this study, these results do suggest that poor adherence due to treatment interruptions may lead to disease progression. Patient adherence to imatinib in GIST has not been formally assessed in a clinical study. However, in patients with chronic myeloid leukemia, poor adherence to imatinib has been shown to have adverse consequences, resulting in suboptimal responses, disease relapse, and higher healthcare utilization and costs.33,38,39 Therefore, efforts to improve adherence may be expected to lead to better patient outcomes.
Barriers to adherence
Numerous factors have been identified as barriers to adherence in patients with chronic diseases.1,40 These factors can be grouped into three categories: patient-related factors, treatment-related factors, and healthcare system-related factors (Figure 2). When considered from a population perspective rather than from the perspective of an individual patient, poor adherence likely reflects a complex interplay among multiple factors.
Patient-related factors
These factors include sociodemographic, psychosocial, and employment status; comorbid conditions; polypharmacy; and social and family support characteristics; as well as the patient’s health beliefs, self-efficacy, and health literacy. Age may be a factor associated with poor adherence, which is particularly problematic among adolescents.41 Older individuals may also be prone to adherence issues for a variety of reasons, including the need to take multiple medications for comorbid conditions, visual and cognitive deficits, lack of social support if living alone, medication cost if living on a fixed budget, and higher risk of side effects due to drug-drug interactions and altered drug pharmacokinetics.42,43 Other demographic factors, such as race, educational level, and socioeconomic status, may indirectly affect adherence due to their impact on access to healthcare.1
Patient expectations are also key factors influencing adherence. On the one hand, patients who are not convinced about the importance of their therapy or who believe that their fate is governed largely by chance are more likely to exhibit poor adherence. 1,40 On the other hand, patients who believe that medication will be effective and that their own actions can influence the course of disease are more likely to adhere to treatment, even when faced with side effects. With these expectations in mind, clinicians can provide relevant information and encouragement and address their patients’ concerns.
Treatment-related factors
These factors include the complexity of the regimen; pill burden; duration of treatment; timing of drug administration; and type, frequency, and severity of side effects. Adherence is negatively affected by more complex regimens, such as those with multiple drugs and those that are inconvenient. 40 Medications that must be taken with respect to meals (eg, with meals or several hours before or after meals) may limit adherence in some patients.
Side effects, or the fear of side effects, have generally been shown to reduce adherence across multiple chronic diseases.40 However, clinical studies in cancer patients provide conflicting evidence about the impact of side effects on adherence.1,44 Side effects may occur early, before treatment benefits become evident, and obviously may be a significant barrier to adherence for some cancer patients. For instance, oral capecitabine is associated with a high incidence of grade 1/2 diarrhea,45 which may be expected to adversely impact adherence, although no data are available to support this theory. Lastly, as previously noted, adherence tends to decrease during long-term treatment.25
Healthcare system-related factors
The patient-provider relationship, along with patient access to and patient satisfaction with medical care, can affect adherence.27,40 Positive, constructive relationships between patients and clinicians are key to minimizing treatment-related anxiety and may improve adherence.46 The high cost of medication may be a major barrier for patients who do not have medical insurance and also for those whose insurance does not provide coverage or requires high copayments for oral anticancer medications. 3,47
Overcoming barriers to adherence in patient management
Set realistic patient expectations on treatment outcomes and side effects
Patient education and a collaborative patient-physician relationship are key components for overcoming barriers to adherence. In cases in which patients cannot afford oral treatment, patient-assistance programs may be helpful. Some patients, however, may refuse educational or assistance programs because they do not want to appear as being needy or as having failed.
Patient-centered education about what patients can expect from treatment— both in terms of benefits and side effects, as well as the steps to take to manage key side effects should they occur—has been shown to improve adherence.46 Realistic expectations about treatment benefits should be offered, as patients may wrongfully conclude that their treatment is not working if their too-high expectations are not met, leading some to stop treatment. Hence, patients on maintenance therapy with targeted drugs, such as erlotinib in non-small cell lung cancer or ridaforolimus in the ongoing SUCCEED trial in bone or soft-tissue sarcomas, should be informed that treatment is designed to keep their disease stable and not necessarily to further shrink the size of their tumors.48
Oral targeted agents may offer an improved tolerability profile compared with cytotoxic chemotherapy but nevertheless may cause specific, dose-limiting side effects related to target inhibition in normal cells (Table 1). Key side effects associated with each prescribed agent, as well as prophylactic steps that can be taken to prevent or minimize potential side effects and instructions to follow should side effects occur, should be discussed with patients before treatment is started.
For example, combined data from nine studies show that patients receiving the standard dose of sorafenib run a significant risk of hypertension.49 Physicians should closely monitor these patients during treatment and prescribe appropriate antihypertensive agents as needed.
An acneiform rash is common with erlotinib and other EGFR-targeting drugs; it is amenable to topical steroid therapy in mild cases and tetracyclines in moderate cases.50 ‘‘Aphthous-like’’ oral lesions are common with mTOR inhibitors, such as temsirolimus (Torisel), everolimus, and ridaforolimus, but they differ from the classic mucositis encountered with cytotoxic chemotherapy.51 Oral ulcerations are often amenable to prophylactic strategies: practicing good oral hygiene with brushing and flossing after each meal, avoiding spicy and acidic foods, drinking warm rather than hot beverages, and cleansing the mouth with baking soda rinses.52
Nausea and vomiting are well recognized side effects associated with cytotoxic chemotherapy and may be problematic with some oral anticancer drugs (Figure 3). Oral agents with a moderate emesis risk (30%–90%) include cyclophosphamide, etoposide, imatinib, and temozolomide (Temodar), and those with a low risk (10%– 30%) include capecitabine, oral fludarabine (Oforta), and pazopanib. 9,53,54 Most orally active targeted agents, except for imatinib, have a very low risk of emesis (ie, < 10%); they include erlotinib, gefitinib, sorafenib, and sunitinib. 54
Several classes of antiemetic agents are available for preventing nausea and vomiting, including serotonin 5-HT3 (5-hydroxytryptamine) agonists (eg, ondansetron, granisetron, dolasetron [Anzemet]), dexamethasone, and the neurokinin-1 (NK1) receptor antagonist aprepitant (Emend).54,55 Each drug is available in an oral formulation, which provides comparable prophylaxis as the corresponding IV formulation.56 Guidelines for prophylactic use of these agents are available for IV chemotherapy drugs and regimens based on their emetic risk.56,57 However, prospective data on the use of these agents during daily dosing with oral anticancer drugs are limited, and therefore treatment is largely empirical. 5
Dose reduction may be an option to manage side effects effectively while allowing patients to remain on treatment. In some cases, side effects may be an indicator of the efficacy of treatment—as in the case of rash with EGFR inhibitors—and the patient should be made aware of this possibility. 58,59
Provide effective patient education
Education can be offered in many formats but should be tailored to patient preferences, whenever possible, with sufficient time made available to assess patient needs and for patients to express concerns and ask questions. It is helpful to include a family member or caregiver who can reinforce educational information at home and encourage the patient to maintain adherence. Patient-oriented written materials and reliable online information sources may be offered to reinforce and supplement learning points made by the healthcare team.
In addition to providing information, clinicians can help to improve patient adherence by offering encouragement and empathy during each interaction with their patients.22,60 Regular follow-up to emphasize the need for adherence, answer additional questions, and obtain feedback about treatment is also an integral part of an effective strategy for promoting adherence. Patients may forget much of what their physicians tell them, particularly when the prognosis is poor.61 This scenario underscores the importance of frequent interactions and written materials for patient reference at home. Follow-up can be provided by periodic telephone calls from the oncology nursing staff or by group educational sessions—the latter should be for patients who have expressed an interest in attending such sessions.25,62