Challenges of ensuring adherence to oral therapy in patients with solid malignancies

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: [email protected].

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

Perform routine monitoring and documentation of adherence
From the provider’s perspective, improvements can be achieved by routine monitoring of patient adherence, as well as assessment and reinforcement of patient understanding of the treatment goals and the need to adhere to treatment recommendations. This process also includes documentation of the patient’s treatment history, whether in written files or electronic medical records. IV chemotherapy drugs are documented in the chemotherapy flow sheet, which is a best clinical practice in oncology. In contrast, oral anticancer agents may be entered into patient records in the same manner as oral drugs used for other medical conditions (eg, antihypertensive drugs). Instead, it is preferable to enter information about oral anticancer agents directly onto the chemotherapy flow sheet as a care plan, including dosage, schedule, and all dosage adjustments. This approach makes the oral agent prominent in the cancer plan and may help to improve adherence through better documentation and patient follow-up.

Use experimental approaches for monitoring/improving adherence
Conventional methods for monitoring adherence, such as patient selfreports, medication diaries, and pill counts, are not always reliable in clinical practice, as already discussed. As a result, a number of other methods are being evaluated to monitor and improve patient adherence.

The feasibility of an automated voice-response system (AVRS) coupled with nursing intervention was recently evaluated in patients with solid tumors who were receiving oral chemotherapy agents.63 Patients received weekly calls from the AVRS and answered questions about adherence as well as the severity of 15 symptoms. Patients reporting adherence below 100% or symptom severity of 4 or higher, on a 0 to 10 scale, for 3 consecutive weeks were called by a nurse for assistance with treatment adherence and symptomatology. In the study cohort, nonadherence to oral chemotherapy was 23.3% and was related to both symptoms and missed or forgotten medication. Notably, better symptom management— and not symptom severity per se—was associated with higher rates of adherence.

Other technologies that may enhance patient adherence to oral drug therapy include daily cell phone alarms, text messages, or smartphone reminder applications. Although the use of text-message reminders requiring a patient response has been shown to increase adherence in patients with human immunodeficiency virus receiving antiretroviral therapy,64 the use of interactive mobile web or smartphone applications to enhance patient adherence to antihypertensive medications is still being investigated. 65

Building on the MEMS strategy, GlowCaps (Vitality, Inc., Cambridge, MA) is a pill bottle cap designed to replace the conventional cap provided by retail pharmacies. The electronic cap flashes and plays a ringtone when it is time for the next dose, and its wireless transmitter sends a signal to a reminder light plug that also flashes. If the cap is not opened, the transmitter dials the patient’s telephone with an additional reminder. The cap also creates weekly adherence reports that can be e‑mailed to a friend or family member, as well as monthly adherence reports that can be mailed to the healthcare provider. The GlowCap should improve adherence for patients who forget to take their medication, but like MEMS, it only measures whether the bottle was opened and not whether the medication was actually taken. Conventional bottle caps are supplied at no additional charge; however, this device carries a retail price of $99, and therefore cost can be an issue for patients on a fixed budget and for those requiring multiple medications.

A miniscule edible “chip” (Proteus Biomedical Inc., Redwood City, CA) may go one step farther by confirming that medication has actually been ingested. The chip, which is a digestible sensor made from food ingredients, is activated by the low pH in the stomach to send a signal to a microelectronic receiver located in a bandagestyle skin patch. The receiver records medication-related information, including the date, time, and dose taken. A pilot study showed that this technology substantially improved adherence for an antihypertensive agent from 30% to 80% over a 6-month period. 66 The cost of the edible chip is only a few cents each when made in large quantities, suggesting that it may be economically viable. The involvement of pharmacists in monitoring prescription refills and in providing patient reminders is also being evaluated for effectiveness (Medco Health Solutions, Inc., Fairfield, OH).

Consider economic issues
Oncologists in the United States are reimbursed for administering IV chemotherapy agents. This reimbursement includes the cost of the medication and an additional small percentage above the acquisition cost (eg, 6% from Medicare). Profit from IV chemotherapy (ie, reimbursement exceeding acquisition costs) may contribute to the financial viability of many oncology practices.67 However, a similar financial incentive for use of oral anticancer agents is not provided by payors, and therefore the current system favors use of IV therapy in cancer management. To rectify this situation, an alternate method will need to be developed to provide comparable incentives for oral anticancer drugs, particularly for those agents that improve patient outcome or reduce healthcare costs.

The added cost of patient education and adherence monitoring— both in terms of oncology staff and time—is another financial issue to be addressed. These costs cannot be borne by oncology practices but will need to be covered by payors or patients. Episode-based or monthly management fees provided by payors, which encompass the coordination of oncology care, may represent viable options for covering patient education and adherence monitoring.67

Conclusion
Oral agents are increasingly used to treat many solid malignancies— both as primary treatment in advanced cancers and as maintenance therapy in patients after response to first-line chemotherapy. In these settings, long-term use of oral agents offers the promise of transforming cancer into a chronic disease. With these changes in treatment regimen and disease state, patient adherence becomes increasingly important. Poor adherence with tamoxifen has already been associated with poor outcomes in women with breast cancer.35 As other oral anticancer agents are used for longer periods, it is likely that additional associations between poor adherence and adverse outcomes will be shown.

Clinicians cannot simply depend on self-reports or pill counts to identify nonadherent patients. Instead, they need to adopt a proactive role, which includes assessing patient needs and understanding, educating patients before initiating treatment, key points at all subsequent visits, and using follow-up phone calls to identify issues that impact adherence. If barriers to adherence are identified, whether attributable to patient, treatment, or healthcare system-related factors, oncologists and their staffs have an opportunity to play an essential role in addressing and reducing, if not eliminating, those barriers. Overcoming adherence barriers should result in better clinical outcomes and improved quality of life for patients with sarcomas and other solid tumors.

Acknowledgments: The author would like to thank Brigitte Teissedre, PhD, and Joseph J. Abrajano, PhD, of Medicus International New York, for editorial assistance in the preparation of this manuscript. Editorial support was funded by Merck & Co., Inc. The author was fully responsible for all content and editorial decisions and received no financial support or other compensation related to the development of this article.

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 44. Richardson JL, Marks G, Levine A. The influence of symptoms of disease and side effects of treatment on compliance with cancer therapy. J Clin Oncol 1988;6:1746–1752.
 45. Walko CM, Lindley C. Capecitabine: a review. Clin Ther 2005;27:23–44.
 46. Fallowfield LJ. Treatment decision- making in breast cancer: the patient-doctor relationship. Breast Cancer Res Treat 2008;112(suppl 1):5–13.
 47. Elliott R. Non-adherence to medicines: not solved but solvable. J Health Serv Res Policy 2009;14:58–61.
 48. Mok TS, Ramalingam SS. Maintenance therapy in nonsmall-cell lung cancer: a new treatment paradigm. Cancer 2009;115:5143– 5154.
 49. Wu S, Chen JJ, Kudelka A, Lu J, Zhu X. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol 2008;9:117–123.
 50. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005;16:1425–1433.
 51. Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer 2010;116:210–215.
 52. Scully C. Clinical practice: aphthous ulceration. N Engl J Med. 2006;355:165–172.
 53. Hurwitz HI, Dowlati A, Saini S, et al. Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 2009;15:4220– 4227.
 54. Jordan K, Sippel C, Schmoll HJ. Guidelines for antiemetic treatment of chemotherapy- induced nausea and vomiting: past, present, and future recommendations. Oncologist 2007;12:1143–1150.
 55. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008;358: 2482–2494.
 56. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006;24:2932–2947.
 57. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Antiemesis. V1. 2010. Available at: http://www.nccn.org. Accessed May 5, 2010.
 58. Perez-Soler R. Rash as a surrogate marker for efficacy of epidermal growth factor receptor inhibitors in lung cancer. Clin Lung Cancer 2006;8(suppl 1):S7–S14.
 59. Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res 2007;13:3913–3921.
 60. Morse DS, Edwardsen EA, Gordon HS. Missed opportunities for interval empathy in lung cancer communication. Arch Intern Med 2008;168:1853–1858.
 61. Jansen J, van Weert J, van der Meulen N, van Dulmen S, Heeren T, Bensing J. Recall in older cancer patients: measuring memory for medical information. Gerontologist 2008;48:149–157.
 62. Moore S. Facilitating oral chemotherapy treatment and compliance through patient/ family-focused education. Cancer Nurs 2007;30:112–122; quiz 123–124.
 63. Decker V, Spoelstra S, Miezo E, et al. A pilot study of an automated voice response system and nursing intervention to monitor adherence to oral chemotherapy agents. Cancer Nurs 2009;32:E20–E29.
 64. Lester RT, Ritvo P, Mills EJ, et al. Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet 2010;376:1838–1845.
 65. Medication Adherence and mHealth: The George Washington University and Wireless Reach Pill Phone Study. Available at: http://multivu.prnewswire.com/mnr/qualcomm/ 48588/docs/48588-PillPhone_CS_FINAL_ r2.pdf. Accessed May 3, 2011.
 66. Saenz A. Ingestible chip that reminds you to take medicine begins trial. Singularity Hub. Available at: http://singularityhub. com/2009/09/24/ingestible-chip-that-remindsyou- to-take-medicine-begins-trials-withnovartis/# more-7574. Accessed April 6, 2010.
 67. Smith TJ, Hillner BE. Concrete options and ideas for increasing value in oncology care: the view from one trench. Oncologist 2010;15(suppl 1):65–72.

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: [email protected].

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

Perform routine monitoring and documentation of adherence
From the provider’s perspective, improvements can be achieved by routine monitoring of patient adherence, as well as assessment and reinforcement of patient understanding of the treatment goals and the need to adhere to treatment recommendations. This process also includes documentation of the patient’s treatment history, whether in written files or electronic medical records. IV chemotherapy drugs are documented in the chemotherapy flow sheet, which is a best clinical practice in oncology. In contrast, oral anticancer agents may be entered into patient records in the same manner as oral drugs used for other medical conditions (eg, antihypertensive drugs). Instead, it is preferable to enter information about oral anticancer agents directly onto the chemotherapy flow sheet as a care plan, including dosage, schedule, and all dosage adjustments. This approach makes the oral agent prominent in the cancer plan and may help to improve adherence through better documentation and patient follow-up.

Use experimental approaches for monitoring/improving adherence
Conventional methods for monitoring adherence, such as patient selfreports, medication diaries, and pill counts, are not always reliable in clinical practice, as already discussed. As a result, a number of other methods are being evaluated to monitor and improve patient adherence.

The feasibility of an automated voice-response system (AVRS) coupled with nursing intervention was recently evaluated in patients with solid tumors who were receiving oral chemotherapy agents.63 Patients received weekly calls from the AVRS and answered questions about adherence as well as the severity of 15 symptoms. Patients reporting adherence below 100% or symptom severity of 4 or higher, on a 0 to 10 scale, for 3 consecutive weeks were called by a nurse for assistance with treatment adherence and symptomatology. In the study cohort, nonadherence to oral chemotherapy was 23.3% and was related to both symptoms and missed or forgotten medication. Notably, better symptom management— and not symptom severity per se—was associated with higher rates of adherence.

Other technologies that may enhance patient adherence to oral drug therapy include daily cell phone alarms, text messages, or smartphone reminder applications. Although the use of text-message reminders requiring a patient response has been shown to increase adherence in patients with human immunodeficiency virus receiving antiretroviral therapy,64 the use of interactive mobile web or smartphone applications to enhance patient adherence to antihypertensive medications is still being investigated. 65

Building on the MEMS strategy, GlowCaps (Vitality, Inc., Cambridge, MA) is a pill bottle cap designed to replace the conventional cap provided by retail pharmacies. The electronic cap flashes and plays a ringtone when it is time for the next dose, and its wireless transmitter sends a signal to a reminder light plug that also flashes. If the cap is not opened, the transmitter dials the patient’s telephone with an additional reminder. The cap also creates weekly adherence reports that can be e‑mailed to a friend or family member, as well as monthly adherence reports that can be mailed to the healthcare provider. The GlowCap should improve adherence for patients who forget to take their medication, but like MEMS, it only measures whether the bottle was opened and not whether the medication was actually taken. Conventional bottle caps are supplied at no additional charge; however, this device carries a retail price of $99, and therefore cost can be an issue for patients on a fixed budget and for those requiring multiple medications.

A miniscule edible “chip” (Proteus Biomedical Inc., Redwood City, CA) may go one step farther by confirming that medication has actually been ingested. The chip, which is a digestible sensor made from food ingredients, is activated by the low pH in the stomach to send a signal to a microelectronic receiver located in a bandagestyle skin patch. The receiver records medication-related information, including the date, time, and dose taken. A pilot study showed that this technology substantially improved adherence for an antihypertensive agent from 30% to 80% over a 6-month period. 66 The cost of the edible chip is only a few cents each when made in large quantities, suggesting that it may be economically viable. The involvement of pharmacists in monitoring prescription refills and in providing patient reminders is also being evaluated for effectiveness (Medco Health Solutions, Inc., Fairfield, OH).

Consider economic issues
Oncologists in the United States are reimbursed for administering IV chemotherapy agents. This reimbursement includes the cost of the medication and an additional small percentage above the acquisition cost (eg, 6% from Medicare). Profit from IV chemotherapy (ie, reimbursement exceeding acquisition costs) may contribute to the financial viability of many oncology practices.67 However, a similar financial incentive for use of oral anticancer agents is not provided by payors, and therefore the current system favors use of IV therapy in cancer management. To rectify this situation, an alternate method will need to be developed to provide comparable incentives for oral anticancer drugs, particularly for those agents that improve patient outcome or reduce healthcare costs.

The added cost of patient education and adherence monitoring— both in terms of oncology staff and time—is another financial issue to be addressed. These costs cannot be borne by oncology practices but will need to be covered by payors or patients. Episode-based or monthly management fees provided by payors, which encompass the coordination of oncology care, may represent viable options for covering patient education and adherence monitoring.67

Conclusion
Oral agents are increasingly used to treat many solid malignancies— both as primary treatment in advanced cancers and as maintenance therapy in patients after response to first-line chemotherapy. In these settings, long-term use of oral agents offers the promise of transforming cancer into a chronic disease. With these changes in treatment regimen and disease state, patient adherence becomes increasingly important. Poor adherence with tamoxifen has already been associated with poor outcomes in women with breast cancer.35 As other oral anticancer agents are used for longer periods, it is likely that additional associations between poor adherence and adverse outcomes will be shown.

Clinicians cannot simply depend on self-reports or pill counts to identify nonadherent patients. Instead, they need to adopt a proactive role, which includes assessing patient needs and understanding, educating patients before initiating treatment, key points at all subsequent visits, and using follow-up phone calls to identify issues that impact adherence. If barriers to adherence are identified, whether attributable to patient, treatment, or healthcare system-related factors, oncologists and their staffs have an opportunity to play an essential role in addressing and reducing, if not eliminating, those barriers. Overcoming adherence barriers should result in better clinical outcomes and improved quality of life for patients with sarcomas and other solid tumors.

Acknowledgments: The author would like to thank Brigitte Teissedre, PhD, and Joseph J. Abrajano, PhD, of Medicus International New York, for editorial assistance in the preparation of this manuscript. Editorial support was funded by Merck & Co., Inc. The author was fully responsible for all content and editorial decisions and received no financial support or other compensation related to the development of this article.

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 18. Twelves C, Gollins S, Grieve R, Samuel L. A randomised cross-over trial comparing patient preference for oral capecitabine and 5-fluorouracil/leucovorin regimens in patients with advanced colorectal cancer. Ann Oncol 2006;17:239–245.
 19. Jensen LH, Osterlind K, Rytter C. Randomized cross-over study of patient preference for oral or intravenous vinorelbine in combination with carboplatin in the treatment of advanced NSCLC. Lung Cancer 2008;62:85–91.
 20. Findlay M, von Minckwitz G, Wardley A. Effective oral chemotherapy for breast cancer: pillars of strength. Ann Oncol 2008;19:212–222.
 21. Pelusi J. Capecitabine versus 5-FU in metastatic colorectal cancer: considerations for treatment decision-making. Commun Oncol 2006;3:19–27.
 22. Pollak KI, Arnold RM, Jeffreys AS, et al. Oncologist communication about emotion during visits with patients with advanced cancer. J Clin Oncol 2007;25:5748–5752.
 23. Palmieri FM, Barton DL. Challenges of oral medications in patients with advanced breast cancer. Semin Oncol Nurs 2007;23(4 suppl 2):S17–S22.
 24. Ingersoll KS, Cohen J. The impact of medication regimen factors on adherence to chronic treatment: a review of literature. J Behav Med 2008;31:213–224.
 25. O’Neill VJ, Twelves CJ. Oral cancer treatment: developments in chemotherapy and beyond. Br J Cancer 2002;87:933–937.
 26. Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health 2008;11:44–47.
 27. Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer treatment. CA Cancer J Clin 2009;59:56–66.
 28. Waterhouse DM, Calzone KA, Mele C, Brenner DE. Adherence to oral tamoxifen: a comparison of patient self-report, pill counts, and microelectronic monitoring. J Clin Oncol 1993;11:1189–1197.
 29. Ziller V, Kalder M, Albert US, et al. Adherence to adjuvant endocrine therapy in postmenopausal women with breast cancer. Ann Oncol 2009;20:431–436.
 30. Hansen RA, Kim MM, Song L, Tu W, Wu J, Murray MD. Comparison of methods to assess medication adherence and classify nonadherence. Ann Pharmacother 2009;43:413–422.
 31. Muss HB, Berry DA, Cirrincione CT, et al. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 2009;360:2055–2065.
 32. Lebovits AH, Strain JJ, Schleifer SJ, Tanaka JS, Bhardwaj S, Messe MR. Patient noncompliance with self-administered chemotherapy. Cancer 1990;65:17–22.
33. Noens L, van Lierde MA, De Bock R, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood 2009;113:5401–5411.
 34. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365:1687–1717.
 35. McCowan C, Shearer J, Donnan PT, et al. Cohort study examining tamoxifen adherence and its relationship to mortality in women with breast cancer. Br J Cancer 2008;99:1763–1768.
 36. Demetri GD, Wang Y, Wehrle E, et al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 2009;27:3141–3147.
 37. Blay JY, Le Cesne A, Ray-Coquard I, et al. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J Clin Oncol 2007;25:1107–1113.
 38. O’Dwyer M, Atallah E. Practical considerations for the management of patients in the tyrosine kinase inhibitor era. Semin Hematol 2009;46(2 suppl 3):S16–S21.
 39. Wu EQ, Johnson S, Beaulieu N, et al. Healthcare resource utilization and costs associated with non-adherence to imatinib treatment in chronic myeloid leukemia patients. Curr Med Res Opin 2010;26:61–69.
 40. Krueger KP, Berger BA, Felkey B. Medication adherence and persistence: a comprehensive review. Adv Ther 2005;22:313–356.
 41. Tebbi CK. Treatment compliance in childhood and adolescence. Cancer 1993;71(10 suppl):3441–3449.
 42. MacLaughlin EJ, Raehl CL, Treadway AK, Sterling TL, Zoller DP, Bond CA. Assessing medication adherence in the elderly: which tools to use in clinical practice? Drugs Aging 2005;22:231–255.
 43. Tam-McDevitt J. Polypharmacy, aging, and cancer. Oncology 2008;22:1052–1055; discussion 1055, 1058, 1060.
 44. Richardson JL, Marks G, Levine A. The influence of symptoms of disease and side effects of treatment on compliance with cancer therapy. J Clin Oncol 1988;6:1746–1752.
 45. Walko CM, Lindley C. Capecitabine: a review. Clin Ther 2005;27:23–44.
 46. Fallowfield LJ. Treatment decision- making in breast cancer: the patient-doctor relationship. Breast Cancer Res Treat 2008;112(suppl 1):5–13.
 47. Elliott R. Non-adherence to medicines: not solved but solvable. J Health Serv Res Policy 2009;14:58–61.
 48. Mok TS, Ramalingam SS. Maintenance therapy in nonsmall-cell lung cancer: a new treatment paradigm. Cancer 2009;115:5143– 5154.
 49. Wu S, Chen JJ, Kudelka A, Lu J, Zhu X. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol 2008;9:117–123.
 50. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005;16:1425–1433.
 51. Sonis S, Treister N, Chawla S, Demetri G, Haluska F. Preliminary characterization of oral lesions associated with inhibitors of mammalian target of rapamycin in cancer patients. Cancer 2010;116:210–215.
 52. Scully C. Clinical practice: aphthous ulceration. N Engl J Med. 2006;355:165–172.
 53. Hurwitz HI, Dowlati A, Saini S, et al. Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 2009;15:4220– 4227.
 54. Jordan K, Sippel C, Schmoll HJ. Guidelines for antiemetic treatment of chemotherapy- induced nausea and vomiting: past, present, and future recommendations. Oncologist 2007;12:1143–1150.
 55. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008;358: 2482–2494.
 56. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006;24:2932–2947.
 57. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Antiemesis. V1. 2010. Available at: http://www.nccn.org. Accessed May 5, 2010.
 58. Perez-Soler R. Rash as a surrogate marker for efficacy of epidermal growth factor receptor inhibitors in lung cancer. Clin Lung Cancer 2006;8(suppl 1):S7–S14.
 59. Wacker B, Nagrani T, Weinberg J, Witt K, Clark G, Cagnoni PJ. Correlation between development of rash and efficacy in patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in two large phase III studies. Clin Cancer Res 2007;13:3913–3921.
 60. Morse DS, Edwardsen EA, Gordon HS. Missed opportunities for interval empathy in lung cancer communication. Arch Intern Med 2008;168:1853–1858.
 61. Jansen J, van Weert J, van der Meulen N, van Dulmen S, Heeren T, Bensing J. Recall in older cancer patients: measuring memory for medical information. Gerontologist 2008;48:149–157.
 62. Moore S. Facilitating oral chemotherapy treatment and compliance through patient/ family-focused education. Cancer Nurs 2007;30:112–122; quiz 123–124.
 63. Decker V, Spoelstra S, Miezo E, et al. A pilot study of an automated voice response system and nursing intervention to monitor adherence to oral chemotherapy agents. Cancer Nurs 2009;32:E20–E29.
 64. Lester RT, Ritvo P, Mills EJ, et al. Effects of a mobile phone short message service on antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet 2010;376:1838–1845.
 65. Medication Adherence and mHealth: The George Washington University and Wireless Reach Pill Phone Study. Available at: http://multivu.prnewswire.com/mnr/qualcomm/ 48588/docs/48588-PillPhone_CS_FINAL_ r2.pdf. Accessed May 3, 2011.
 66. Saenz A. Ingestible chip that reminds you to take medicine begins trial. Singularity Hub. Available at: http://singularityhub. com/2009/09/24/ingestible-chip-that-remindsyou- to-take-medicine-begins-trials-withnovartis/# more-7574. Accessed April 6, 2010.
 67. Smith TJ, Hillner BE. Concrete options and ideas for increasing value in oncology care: the view from one trench. Oncologist 2010;15(suppl 1):65–72.

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: [email protected].

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

Perform routine monitoring and documentation of adherence
From the provider’s perspective, improvements can be achieved by routine monitoring of patient adherence, as well as assessment and reinforcement of patient understanding of the treatment goals and the need to adhere to treatment recommendations. This process also includes documentation of the patient’s treatment history, whether in written files or electronic medical records. IV chemotherapy drugs are documented in the chemotherapy flow sheet, which is a best clinical practice in oncology. In contrast, oral anticancer agents may be entered into patient records in the same manner as oral drugs used for other medical conditions (eg, antihypertensive drugs). Instead, it is preferable to enter information about oral anticancer agents directly onto the chemotherapy flow sheet as a care plan, including dosage, schedule, and all dosage adjustments. This approach makes the oral agent prominent in the cancer plan and may help to improve adherence through better documentation and patient follow-up.

Use experimental approaches for monitoring/improving adherence
Conventional methods for monitoring adherence, such as patient selfreports, medication diaries, and pill counts, are not always reliable in clinical practice, as already discussed. As a result, a number of other methods are being evaluated to monitor and improve patient adherence.

The feasibility of an automated voice-response system (AVRS) coupled with nursing intervention was recently evaluated in patients with solid tumors who were receiving oral chemotherapy agents.63 Patients received weekly calls from the AVRS and answered questions about adherence as well as the severity of 15 symptoms. Patients reporting adherence below 100% or symptom severity of 4 or higher, on a 0 to 10 scale, for 3 consecutive weeks were called by a nurse for assistance with treatment adherence and symptomatology. In the study cohort, nonadherence to oral chemotherapy was 23.3% and was related to both symptoms and missed or forgotten medication. Notably, better symptom management— and not symptom severity per se—was associated with higher rates of adherence.

Other technologies that may enhance patient adherence to oral drug therapy include daily cell phone alarms, text messages, or smartphone reminder applications. Although the use of text-message reminders requiring a patient response has been shown to increase adherence in patients with human immunodeficiency virus receiving antiretroviral therapy,64 the use of interactive mobile web or smartphone applications to enhance patient adherence to antihypertensive medications is still being investigated. 65

Building on the MEMS strategy, GlowCaps (Vitality, Inc., Cambridge, MA) is a pill bottle cap designed to replace the conventional cap provided by retail pharmacies. The electronic cap flashes and plays a ringtone when it is time for the next dose, and its wireless transmitter sends a signal to a reminder light plug that also flashes. If the cap is not opened, the transmitter dials the patient’s telephone with an additional reminder. The cap also creates weekly adherence reports that can be e‑mailed to a friend or family member, as well as monthly adherence reports that can be mailed to the healthcare provider. The GlowCap should improve adherence for patients who forget to take their medication, but like MEMS, it only measures whether the bottle was opened and not whether the medication was actually taken. Conventional bottle caps are supplied at no additional charge; however, this device carries a retail price of $99, and therefore cost can be an issue for patients on a fixed budget and for those requiring multiple medications.

A miniscule edible “chip” (Proteus Biomedical Inc., Redwood City, CA) may go one step farther by confirming that medication has actually been ingested. The chip, which is a digestible sensor made from food ingredients, is activated by the low pH in the stomach to send a signal to a microelectronic receiver located in a bandagestyle skin patch. The receiver records medication-related information, including the date, time, and dose taken. A pilot study showed that this technology substantially improved adherence for an antihypertensive agent from 30% to 80% over a 6-month period. 66 The cost of the edible chip is only a few cents each when made in large quantities, suggesting that it may be economically viable. The involvement of pharmacists in monitoring prescription refills and in providing patient reminders is also being evaluated for effectiveness (Medco Health Solutions, Inc., Fairfield, OH).

Consider economic issues
Oncologists in the United States are reimbursed for administering IV chemotherapy agents. This reimbursement includes the cost of the medication and an additional small percentage above the acquisition cost (eg, 6% from Medicare). Profit from IV chemotherapy (ie, reimbursement exceeding acquisition costs) may contribute to the financial viability of many oncology practices.67 However, a similar financial incentive for use of oral anticancer agents is not provided by payors, and therefore the current system favors use of IV therapy in cancer management. To rectify this situation, an alternate method will need to be developed to provide comparable incentives for oral anticancer drugs, particularly for those agents that improve patient outcome or reduce healthcare costs.

The added cost of patient education and adherence monitoring— both in terms of oncology staff and time—is another financial issue to be addressed. These costs cannot be borne by oncology practices but will need to be covered by payors or patients. Episode-based or monthly management fees provided by payors, which encompass the coordination of oncology care, may represent viable options for covering patient education and adherence monitoring.67

Conclusion
Oral agents are increasingly used to treat many solid malignancies— both as primary treatment in advanced cancers and as maintenance therapy in patients after response to first-line chemotherapy. In these settings, long-term use of oral agents offers the promise of transforming cancer into a chronic disease. With these changes in treatment regimen and disease state, patient adherence becomes increasingly important. Poor adherence with tamoxifen has already been associated with poor outcomes in women with breast cancer.35 As other oral anticancer agents are used for longer periods, it is likely that additional associations between poor adherence and adverse outcomes will be shown.

Clinicians cannot simply depend on self-reports or pill counts to identify nonadherent patients. Instead, they need to adopt a proactive role, which includes assessing patient needs and understanding, educating patients before initiating treatment, key points at all subsequent visits, and using follow-up phone calls to identify issues that impact adherence. If barriers to adherence are identified, whether attributable to patient, treatment, or healthcare system-related factors, oncologists and their staffs have an opportunity to play an essential role in addressing and reducing, if not eliminating, those barriers. Overcoming adherence barriers should result in better clinical outcomes and improved quality of life for patients with sarcomas and other solid tumors.

Acknowledgments: The author would like to thank Brigitte Teissedre, PhD, and Joseph J. Abrajano, PhD, of Medicus International New York, for editorial assistance in the preparation of this manuscript. Editorial support was funded by Merck & Co., Inc. The author was fully responsible for all content and editorial decisions and received no financial support or other compensation related to the development of this article.

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