Adherence to Oral Cancer Therapy in Older Adults: the International Society of Geriatric Oncology (SIOG) Taskforce Recommendations

Cancer Treatment Reviews 57 (2017) 58–66

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Cancer Treatment Reviews

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General and Supportive Care Adherence to oral cancer therapy in older adults: The International Society of Geriatric Oncology (SIOG) taskforce recommendations

Anna Rachelle Mislang a,b, Tanya M. Wildes c, Ravindran Kanesvaran d, Capucine Baldini e, Holly M. Holmes f, ⇑ Ginah Nightingale g, Annemarie Coolbrandt h,i, Laura Biganzoli a, a Medical Oncology Department, Nuovo Ospedale-Santo Stefano, Instituto Toscano Tumori, Prato 59100, Italy b Cancer Clinical Trials Unit, Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, SA 5000, Australia c Division of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA d Division of Medical Oncology, National Cancer Centre Singapore, Singapore e Medical Hospital Huriez, University Lille Nord de France, Lille, France f Division of Geriatric and Palliative Medicine, University of Texas McGovern Medical School, Houston, TX, USA g Department of Pharmacy Practice, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA, USA h Oncology Nursing Department, University Hospitals Leuven, Leuven, Belgium i Academic Center for Nursing and Midwifery, Department of Public Health and Primary Care, KU Leuven, Kapucijnenvoer 35, Box 7001, 3000 Leuven, Belgium article info abstract

Article history: There is an increasing trend towards using oral systemic therapy in patients with cancer. Compared to par- Received 1 April 2017 enteral therapy, oral cancer agents offer convenience, have similar efﬁcacy, and are preferred by patients, Received in revised form 5 May 2017 consequently making its use appealing in older adults. However, adherence is required to ensure its efﬁ- Accepted 6 May 2017 cacy and to avoid compromising treatment outcomes, especially when the treatment goal is curative, or in case of symptomatic/rapidly progressing disease, where dose-intensity is important. This opens a new challenge for clinicians, as optimizing patient adherence is challenging, particularly due to lack of consen- Keywords: sus and scarcity of available clinical evidence. This manuscript aims to review the impact of age-related Adherence factors on adherence, summarize the evidence on adherence, recommend methods for selecting patients Geriatric oncology Oral cancer agents suitable for oral cancer agents, and advise monitoring interventions to promote adherence to treatment. Toxicity Ó 2017 Published by Elsevier Ltd.

Introduction prevalent [10]. Across diseases, adherence has been cited as the single most important modifiable factor that compromises treatment Oral cancer agents (OCA) are changing the treatment paradigm outcomes [11] and yet, besides the variable adherence rates in oncology [1]. As new OCA continue to be developed [2], their use reported on endocrine therapy for breast cancer, there remains lim- is expected to grow further with more patients preferring oral to ited evidence presenting the adherence rates to OCA. This is con- parenteral therapy [3–6]. This is driven by the advantages provided cerning, as most clinical trials on oral therapy do not routinely to both patients and healthcare providers [7–9], which makes include means to measure, predict or monitor adherence [12].To them an appealing option also for older adults. However, there address this issue, the International Society of Geriatric Oncology are also potential challenges [7–9] and concerns about non- formed a task force to review the impact of age-related factors on adherence may be compounded by age-related factors. Table 1 adherence, summarize the evidence on adherence to OCA, and rec- summarizes the potential advantages and disadvantages of oral ommend an algorithm for selecting suitable patients and tools to versus parenteral chemotherapy. measure and monitor adherence to treatment. The outcome is pre- Adherence is crucial for the success of OCA use in any age group, sented in this article. though particularly complicated and potentially more problematic in older patients as factors other than age that contributes to non- adherence (i.e. polypharmacy, cognitive impairment, comorbidities, Oral systemic therapy and adherence drug toxicities, regimen complexity and financial barriers) are more Definition of terms

⇑ Corresponding author. E-mail addresses: [email protected] , [email protected] Medication adherence pertains to the degree or extent of (L. Biganzoli). conformity to the recommended day-to-day treatment by the http://dx.doi.org/10.1016/j.ctrv.2017.05.002 0305-7372/Ó 2017 Published by Elsevier Ltd.

Table 1 Potential advantages and disadvantages of oral versus parenteral cancer therapy in older adults.

Advantages Convenience Fewer clinic visits Flexibility in timing and location of administration Improved patient autonomy Better subjective feeling of control over disease Enhanced sense of empowerment Less amount of time spent in the hospital Prolonged drug exposure Non-invasive Avoids morbidity of long-term intravenous access No difficulties with intravenous cannulation Reduced use of health-care resources for in- and out-patient services Disadvantages Greater risk for polypharmacy and drug interactions Issues with drug bioavailability Efficacy may be compromised in patients with impairment in gastric absorption or motility Instructions required for administration may be complicated, especially for patients with cognitive impairment and inadequate social support Issues with adherence Non-adherence reduces drug efficacy, increases treatment failure and early discontinuation of therapy Over-adherence increases risk for life-threatening toxicities and treatment intolerance Less support from meeting other patients Can potentially lead to social isolation Direct responsibility to treatment may become overwhelming Lesser health-care supervision Higher risk for medication administration errors Less monitoring of toxicities Needs reliable patients, careful counselling, education on cytotoxic safe handling, and assistance on how to identify, manage, and report side effects promptly health-care provider with respect to timing, dosing, and frequency potentially be added to measure the drug in the blood or urine, [11,13,14]. It is measured over a period of time and reported as a although the level may be altered by various dietary and pharma- percentage. Adherence has 3 components: initiation, defined as cokinetic parameters. Electronic medication devices, i.e. medica- the first time the patient takes the initial dose of a prescribed med- tion event monitoring system (MEMS), a pillbox containing an ication; implementation, defined as the fidelity to the prescribed electronic processor that records all time-points at which the box dosing regimen from the time of initiation to the final dose; and is opened, may be used. The 8-item Morisky Medication Adherence discontinuation, defined as the end of the therapy, when the next Scale (MMAS-8) is a reliable, cheap, and easy to use self-reported dose was omitted or ceased, either by the patient or the physician tool, used to assess intentional and non-intentional non- [15]. Primary adherence is the initial event assessing whether the adherence with a score of <6, 6–7, 8 categorized as low, medium, patient received the first prescription or not, while secondary and high adherence, respectively and may be used to screen for adherence is an ongoing process measuring whether the patient potential problems and to monitor adherence over the course of received refills as prescribed or not during a defined observation treatment [17,18]. Although MMAS-8 has been validated in many period [16]. Secondary adherence may be gauged using the gap chronic conditions, it’s use in the oncology setting remains limited. and possession measures, defined respectively as the gap in days This highlights the considerable research gap between validated or the number of days of medication possession between the initial tools to measure medication adherence in the setting of OCA and drug refill and the end of the measurement period [16]. Secondary in older adults with cancer with pre-existing polypharmacy for adherence is considered inadequate if the gap measure is 20% or chronic conditions, as adherence to long-term medications may the possession measure is 80% [16], based on convention rather not equate to adherence to OCA. than measures of predictive validity, depending on the disease There remains no gold standard for measuring/monitoring state. Persistence refers to the act of continuing the treatment for adherence and therefore, no single method could be recom- the prescribed duration, measured from the time of drug initiation mended. Until then, assessment of adherence using combined to discontinuation [13], provided that the patient can obtain the resources, including pharmacy database, MEMS, pill diaries, pill medication. Early-stage persistence includes patients with at least counting, in addition to questionnaires, patient-report and clini- 2 refills while later-stage persistence includes patients who had 3 cian assessment is acceptable. refills of the prescribed drug [16]. These terms will be used for the purpose of this manuscript. Rates and predictors of non-adherence in older patients to oral cancer agents Measures of adherence Age-related factors impacting adherence Adequate adherence is necessary to achieve a favorable health outcome. Ratings from subjective questionnaires on adherence The reasons for non-adherence are usually influenced by factors behavior of patients present potential problems with inaccuracy, that are often multifactorial, complex, dynamic and inter-related overestimation, and lack of standardization. Objective strategies [19]. Older people have more risk factors for non-adherence [20]. may also present similar drawbacks. Pill-counting during clinic vis- Factors having negative impact on adherence [11,21,22] are sum- its can lead to counting inaccuracies and lacks information on marized in Table 2. Most adherence studies are based on the man- dosage timing and patterns of missed dosage. Access to pharmacy agement of many chronic conditions including cancers, among databases, although a useful resource to monitor if prescriptions different age groups. Nevertheless, older patients with cancer are are initially filled, refilled, and prematurely discontinued, does also influenced by age-specific factors that may lead to reduction not guarantee use despite obtaining the drug [11], and may there- in life expectancy, health-related quality of life, and tolerance to fore overestimate adherence. Non-toxic biological markers can medical interventions. These factors are better identified with

Table 2 long-term use [11]. Patients with chronic conditions have been Potential barriers and proposed intervention strategies to improve adherence reported to take only half of their prescribed medications [11,27]. (modified & adapted [11,21,22]). Adding more oral drugs with cycle-specific dose, frequency, and Determinants Potential barriers Intervention strategies duration may augment the complexity and non-adherence. A of adherence recent retrospective cohort study on 21,255 women (57% Patient- Age, gender, education, Self-management programs >55 years) with breast cancer has reported that those who were related (health) literacy, ethnicity, such as patient education, adherent and non-adherent to their long-term medications had a factors marital status, cognitive toxicity-monitoring, 9.8% and 23.1% non-adherence rate to hormonal therapy, respec- function, comorbidities, integrated behavioral, health beliefs, mental health motivational & educational tively [28]. status, history of non- interventions, & social Physiological and structural changes brought by the aging pro- adherence, alcohol and support; combined reminder cess to various organ systems can significantly alter the drug meta- substance abuse (prefilled or blister bolism, leading to prolonged plasma elimination half-life, thereby packaging) with technological (SMS, audio- increasing drug sensitivity [29]. These age-related potential drug visual calls, etc.) strategies interactions (PDI) negatively affect adherence [11,30,31]. Increased Elderly- Cognitive deficits, As per patient-related rates of PDI and substantial association between high-level PDI and specific Visual/hearing/functional factors; Simplify regimen; risk of non-hematological toxicity from chemotherapy were noted factors impairment, comorbidities, adherence programs; in a retrospective study of cancer patients aged 70 years [32]. geriatric syndromes, higher caregiver participation & treatment toxicity, education; domicillary care; Drug-food interactions also need to be considered as certain drugs polypharmacy, financial admission to supported and diet when taken concomitantly with OCA may either reduce burden aged-care facility absorption, altering the efficacy or delay elimination, enhancing Socio- Socio-economic status, Government subsidized or toxicity [33]. Hence, understanding of possible drug-drug and economic family support and insurance covered drugs; factors supervision, quality of referral to social service; drug-food interactions, in addition to any comorbidities that may caregiver, social stigma of reduce out-of-pocket cost potentially interfere with systemic therapy causing exaggerated disease, cost of drugs and toxicity is very important [34]. treatment, employment Drug toxicity is probably the most common cause of premature status discontinuation [35–39]. Toxicities can be potentially debilitating, Disease- Disease severity, Patient education; symptom related uncontrollable symptoms, management; continuous if not life-threatening, as with capecitabine [40], where diarrhea factors psychological component, monitoring and could lead to dehydration, mucositis to malnutrition, and hand- disease duration, disease reassessment foot-syndrome to functional impairment. While most patients will affecting cognition/ discontinue their medication due to toxicities, some patients may understanding Therapy- Treatment toxicity/adverse Simplify regimen; provide opt not to readily disclose any untoward symptoms, causing related events/duration, regimen clear, printed instructions; over-adherence. factors complexity, drug synchronized prescription effectiveness refills; continuous Evidence of adherence to oral cancer agents in older patients reassessment of treatment efficacy and toxicity Despite the increasing use of OCA and substantial concerns Health-care Drug supply and availability, Government subsidized or team patient-provider insurance covered drugs; about adherence and compromised outcomes, there is insufficient factors relationship, insufficient or adequate communication; data to estimate adherence to most oral systemic therapy, as many unclear drug information, shared decision-making; clinical trials and studies on actual clinical practice did not include communication barriers, training health-care routine assessment of adherence when OCA were used [12]. While follow-up arrangements professionals it is difficult to ascertain adherence, it is clear that a considerable number of patients do struggle to adhere to their medications. In comprehensive geriatric assessment to define the overall health a systematic literature review consisting of 63 papers from 2003 status. Addressing potentially modifiable risk factors for non- to 2015 on rates and interventions to improve adherence to oral adherence may enhance patient adherence and maintain long- antineoplastic therapies, adherence rates varied from 46 to 100% term persistence to prescribed therapies [21]. depending on the patient sample, medication type, follow-up per- The cost of many novel anticancer agents can be prohibitive if iod, assessment measure, and calculation of adherence, while only not subsidized by the government or insurance provider, creating 3 out of 12 intervention studies showed improved adherence, lim- financial barriers to adherence in older adults with limited or fixed ited by high-risk of bias [41]. Rates and predictors of non- income. adherence from several studies that included older patients Cognitive, visual, and functional impairments challenge the (65 years) prescribed with OCA are summarised in Table 3.In ability to adhere to complex regimens needed to treat multiple the majority of these clinical trials on various cancer types, treat- medical problems in older adults [23]. In a study of 111 older ment discontinuation or withdrawal have been largely attributed patients (73.5 ± 8.3 years) treated with anticoagulants for atrial to toxicity, particularly in older patients. fibrillation, older age and lower Mini-Mental Status Examination score (<23) were predictive of lower adherence rates on multivari- Consequences of poor adherence ate analyses, showing that cognitive impairment is an independent determinant of adherence to drug therapy in older patients [24]. Adherence improves the effectiveness of interventions while Similarly, the Co-STAR study found that subtle cognitive impair- non-adherence reduces the optimal clinical therapeutic benefit ments in older women without the diagnosis of dementia were and escalates health-care costs [14,42]. Non-adherence has also associated with OCA non-adherence [25]. been associated with increased mortality. Among women with Other factors diminishing adherence are multimorbidity and breast cancer who discontinued endocrine therapy early or who polypharmacy, defined as the concurrent use of 5 medications did not adhere to treatment plan, there was a significantly lower [26]. General age-related conditions (i.e. metabolic, musculoskele- 10-year overall survival (OS) [43] and reduced disease-free survival tal, cardiovascular, and renal diseases) are common in older (DFS) [44,45]. Similarly, the 5- and 10-year OS and DFS were also patients and are usually managed with medications intended for significantly reduced in non-adherent men with breast cancer

Downloaded for Anonymous User (n/a) at South Australia Department of Health from ClinicalKey.com.au by Elsevier on October 24, 2017. For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. Table 3 Summary of studies including older adults on adherence rates to oral cancer agents.

Drug, Author, Year Study design Method of Study population Results Factors associated with Disease (Reference) adherence n (%) non-persistence/ non- adherence

Downloaded for Anonymous User(n/a) atSouth Australia Department ofHealth fromClinicalKey.com.au by Elsevieron October 24,2017. ET Brito et al., 2014 Retrospective database Pharmacy 5861 Non-adherent: Advanced stage Breast [63] dispensing records <70: 4635 (79) 70: 21.6% Alcohol intake 70: 1226 (21) Chemotherapy Hospitalizations Chirgwin et al., Prospective observational Global score 6144 Non-persistent: 18.9% Sequential treatment

For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. 2016 [44] created based on Non-adherent: 5.1% Adverse events dispensed packs Compliance score <90% was Older age 70 associated with reduced Smoking DFS Node-negative Prior thromboembolic event Danilak & Retrospective database Pharmacy 346 Discontinued <2 years: 23% No chemotherapy Chambers, 2012 dispensing records <75: 297 (86) Persisted >2 years: 76% Early discharge from cancer [64] 75: 49 (14) Adherent: 93% care 20% discontinued early due 58–66 (2017) 57 Reviews Treatment Cancer / al. et Mislang A.R. to side effects Fink et al. 2004 Convenience sample Medical records & 518 Non-adherent at 2-yrs: 17% Neutral or negative beliefs [65] phone interviews 65–69: 112 (22) on value of tamoxifen >70: 406 (78) Node-positive Font et al., 2012 Retrospective database Self-reports from 692 Adherent at 5 years: Young age <50 [66] patient & <75: 602 (87) Self-report: 92% Non-sequential treatment physician 75: 90 (13) Physician-report: 94.7% Pharmacy Pharmacy database 74.7% database He et al., 2015 [67] Retrospective database Cancer registry, 3395 Non-adherent: 51% Family history of ovarian drug registry, self- 65: 1183 (35) cancer report Age <40 questionnaire CCI 2 Drugs: analgesics, sedatives, GI Switching ET Hershman et al., Retrospective database Pharmacy 8769 By 4.5 years Age <40 2010 [68] database <65: 5081 (58) Discontinued: 32% Lumpectomy 65: 3866 (42) Non-adherent: 28% Comorbidities Hershman et al., Retrospective database Pharmacy 8769 Estimated 10-year survival 2011 [43] database C vs. DC: 80.7% vs. 73.6% (p < 0.001) A vs. NA: 81.7% vs. 77.8% Retrospective database Pharmacy, 4226 (pAt< 0.001)2 years: Branded drug Hershman et al., prescription <65: 3098 (73) Discontinued: 73% Higher co-payment 2014 [69] database 66–75: 728 (17.5) <65: 76% >75: 400 (9.5) 66–75: 71.8% >75: 54.5% Adherent: 75% <65: 75% 66–75: 76% >75: 60% Hershman, et al., Retrospective database Insurance claims 10,302 Non-adherent: 2473 (25%) Black race 2015 [70] database 65: 8201 (79.6) >65: 21% Advanced age >65: 2103 (20.4) Comorbidities Economic factors (continued on next page) 61 62 Table 3 (continued)

Drug, Author, Year Study design Method of Study population Results Factors associated with Disease (Reference) adherence n (%) non-persistence/ non- adherence Hsieh et al., 2014 Retrospective database Insurance 30,573 Mean follow-up Interruption: [71] database <70: 27826 (91) 4 ± 2.1 years for 70 Tamoxifen only

Downloaded for Anonymous User(n/a) atSouth Australia Department ofHealth fromClinicalKey.com.au by Elsevieron October 24,2017. 70: 2747 (9) Persisted: 9.4% Age <50 Interrupted: 6.4% Non-adherence: Adherent: 9.7% AI only Non-adherent: 6.5% Both interruption & non-

For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. adherence increase all- cause mortality (HR 3.28, CI 2.84–3.79, p < 0.0001) Hsieh et al., 2015 Retrospective cohort Insurance 32,311 Median follow-up time: Younger age [72] database <50: 14,950 (46.3) 4.2 years for 70 Adverse events 50–60: 14,379 (44.5) Non-adherent: 11.7%

70: 2982 (9.2) 58–66 (2017) 57 Reviews Treatment Cancer / al. et Mislang A.R. Neugut et al., 2011 Retrospective cohort Pharmacy & <65: 8110 Non-persistent: Older age [73] medical claims 65: 14,050 <65: 21.1% Prescriptions from non- database 65: 24.7% oncologist Non-adherent: Higher co-payment <65: 10.6% 65: 8.9% Owusu et al., 2008 Retrospective cohort 65 Automated 961 Non-adherent at 5 years: Age 75 [74] pharmacy records 65–74: 635 (66) 49.4% "CCI at 3 years from 75: 326 (34) diagnosis "cardiopulmonary comorbidities at 3 years Indeterminate ER-status Breast conserving surgery without radiotherapy Trabulsi et al., Retrospective database Provincial cancer All 65: 4715 Mean MPR: 83.5% Older age 2014 [75] registry & mean age: 72.9 years 5-year MPR 80%: 79% Non-breast cancer-related Administrative Cumulative probability of hospitalizations claims data discontinuation: 33.8% In-situ disease ConcomitantTamoxifen antidepressant use Switching ET Adding new medications Xu et al.; 2012 Prospective observational Provincial system 116 men Adherence Treatment duration [46] Database <60: 70 (60.3) at 1 yr: 64.6% Low social support 60: 46 (39.7) at 2 yr: 46.4% Younger age at 3 yr: 28.7% Side-effects at 4 yr: 25.8% at 5 yr: 17.7% 5-yr,10-yr OS (p = 0.008) adherent: 97.9%, 79.6% non-adherent: 84.7%, 50.4% 5-yr, 10-yr DFS (p = 0.007) adherent: 95.4%, 72.8% non-adherent: 72.6%, 42.3% Patridge et al., Prospective observational MEMS 161 Adherent: 78% Node-negative Capecitabine Breast 2010 [76] median age: 71 years (65–89) Mastectomy

Breast or CRC De Figueiredo Jr. Prospective cohort Interviews & Pill- 30 Adherent Dyspnea severity et al., 2014 [77] counting mean age: 60.2 years MBC: 96.2% > 60: 63.3% mCRC: 88.3% Table 3 (continued)

Drug, Author, Year Study design Method of Study population Results Factors associated with Disease (Reference) adherence n (%) non-persistence/ non- adherence nmCRC: 90.4%

Downloaded for Anonymous User(n/a) atSouth Australia Department ofHealth fromClinicalKey.com.au by Elsevieron October 24,2017. RC: 94.3% Breast or GI Winterhalder Prospective cohort Self-report 177 Adherent: 91% Side-effects et al., 2010 [78] GI: 81% Forgetting to take treatment Breast: 19% Misunderstanding Mean age: 66 years (55–77) instructions

For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. CRC Seal et al., 2016 Retrospective database Management 6780 Adherent to capecitabine: CCI 9 [79] claims database >65: 480 (7) 52% "Lines of chemotherapy IV chemotherapy: 75% Various cancers Krolop et al., 2013 Prospective observational MEMS 73 Initially non-adherent: - [80] 70: 52 (71) 20.5% >70: 21 (29) >70: 8% Ruddy et al., 2012 Prospective observational Self-report via 317 Persistence: 65% Node-negative CMF (oral cyclophosphamide) Breast [81] medication Median age: 73 years (65–88) Average adherence across Adverse events

calendars all cycles: 97% 58–66 (2017) 57 Reviews Treatment Cancer / al. et Mislang A.R. Self-reported non- adherence: 5% Erlotinib Timmers et al., Prospective observational MEMS 62 Mean adherence: 96.8 ± 4% Older age Lung 2015 [82] Blood tests Median age: 62 years (46–80) Non-persistent: 31% due to Ocular symptoms side effects Stomatitis Imatinib Halpern et al., Retrospective cohort Administrative 465 Mean adherence at 1-yr - GIST or CML 2009 [42] claims GIST: 19.5% GIST: 76.6% 65: 16% Average adherence over entire follow-up period: 66.6% Increased health care utilization and cost outcomes Lafeuille et al., Retrospective database Administrative Based on 2 datasets: 3743 Mean adherence: 93% - Abiraterone Prostate 2014 [83] health-care claims mean age: 72.2 years & databases 65: 2343 (62.5) Bicalutamide Grundmark et al., Retrospective database Pharmacy registry 1406 Adherence at 3 years: 60% Age 75 Prostate 2012 [84] database <65: 163 (11.6) <65: 114 (70) Less severe disease 65: 1243 (88.4) 65: 735 (59)

Adherence: medication possession ratio of 80%. Non-persistence: prescription supply gap of >45 days without subsequent reﬁll. A vs. NA: adherent vs. non-adherent; AI: aromatase inhibitors; C vs. DC: continued vs. discontinued; CCI: Charlson comorbidity index; DFS: disease-free survival; ET: endocrine therapy; ER: estrogen receptor; IV: intravenous; MBC: metastatic breast cancer; MEMS: microelectronic monitoring system; mCRC: metastatic colorectal cancer; nmCRC: non-metastatic colorectal cancer; MPR: medication possession ratio; OS: overall survival; RC: rectal cancer. 63 64 A.R. Mislang et al. / Cancer Treatment Reviews 57 (2017) 58–66

Fig. 1. Management considerations when initiating oral cancer agents in older patients.

[46]. Although heterogeneity from patient, disease, and treatment Promoting adherence to oral therapy factors could contribute to worse outcomes, poor adherence to OCA has been consistently associated with lower likelihood of Optimizing patient adherence, monitoring and managing toxic- response to therapy and higher mortality [41]. However, selection ities from OCA use in the outpatient setting can be challenging for bias cannot be excluded, as patients with a higher risk of death clinicians. Explicit monitoring of toxicities to implement timely might be more likely to become non-adherent, contributing to dose adjustments or discontinuation are crucial and may be the association between non-adherence and worse outcomes. regarded as a useful intervention strategy to ensure adherence. Medication adherence is not solely the responsibility of the Interventions to promote adherence patient, as it is clearly also influenced by other factors as shown in Table 2. Specific interventions to improve adherence are summarised in Doctors with poor communication skills were associated with a Table 2. There is no single adherence-enhancing strategy that is 19% higher risk of patient non-adherence [49]. However, physi- more effective than the other and therefore, a single technique cians communication training significantly improved adherence should not be relied upon as a sole moderator of adherent behav- [49]. A patient-provider interaction addressing the patient’s beliefs ior, but rather integrated within a complex intervention [47]. about the risks and benefits of medications is essential, as this may help the patient understand the rationale for therapy and the likely Patient selection for oral therapy in older adults toxicities [50], give the clinician the opportunity to know the patient’s perspectives, identify potentially modifiable barriers Identifying potential barriers to adherence are extremely and provide interventions, and impart knowledge on disease recur- important in selecting older patients who would benefit from rence to increase adherence [50]. Reduced health-care cost with OCA [48] in order to implement interventions promptly. Clinicians the use of generic medications may also attenuate non- may advise against use of oral agents if adherence cannot be deter- adherence [51], especially in areas lacking government subsidized mined, modified, or monitored, if the risk of toxicity outweighs the or insurance covered medical expenses. perceived benefit, or if pharmacodynamic interactions are unpre- Thus, promoting adherence to oral therapy requires a method- dictable. OCA may not be recommended for patients who lack ical approach to selecting patients who are appropriate for oral motivation, who are non-adherent to other chronic medications, therapy, as well as patient education, monitoring and support that and who have poor understanding of the treatment rationale, heavily relies on inter-professional teamwork among physicians, despite best efforts, to provide appropriate medication education nurses, pharmacists, and other health-care providers involved in and instructions for self-administration. Management considera- the patient care. tions when considering OCA in older patients are illustrated in There is strong evidence suggesting that self-management pro- Fig. 1. grams offered to patients with chronic diseases improve health

Downloaded for Anonymous User (n/a) at South Australia Department of Health from ClinicalKey.com.au by Elsevier on October 24, 2017. For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. A.R. Mislang et al. / Cancer Treatment Reviews 57 (2017) 58–66 65 status and reduce health-care costs [11,52]. Self-management References interventions may include patient education, self-monitoring for toxicity, support for decision-making, psychological and social [1] Bedell CH. A changing paradigm for cancer treatment: the advent of new oral chemotherapy agents. Clin J Oncol Nurs 2003;7(Suppl. 6):5–9. needs [52]. Combining self-management and health-care led [2] Weingart SN, Brown E, Bach PB, et al. NCCN Task Force Report: oral adherence programs can lead to significant improvements in chemotherapy. J Natl Compr Canc Netw 2008;6(Suppl. 3):S1–S14. health-promoting behaviors, communication, cognitive, symptom [3] Partridge AH, Avorn J, Wang PS, et al. Adherence to therapy with oral and disability management. While there is limited information antineoplastic agents. J Natl Cancer Inst 2002;94(9):652–61. [4] Goodin S. Oral chemotherapeutic agents: understanding mechanisms of action that patient education can enforce drug adherence [53,54], increas- and drug interactions. Am J Health Syst Pharm 2007;64(9 Suppl 5):S15–24. ing health awareness and sense of self-efficacy may increase [5] Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral vs adherence, especially when patients are aware of the consequences intravenous palliative chemotherapy. J Clin Oncol: Off J Am Soc Clin Oncol 1997;15(1):110–5. of non-adherence. Nurses and pharmacists may help educate [6] Gornas M, Szczylik C. Oral treatment of metastatic breast cancer with patients and implement an early, aggressive adverse event preven- capecitabine: what influences the decision-making process? Eur J Cancer tion and management strategies to help maximize adherence Care (Engl) 2010;19(1):131–6. [7] Findlay M, von Minckwitz G, Wardley A. Effective oral chemotherapy for breast [55,56]. Several studies have shown that reminder packaging cancer: pillars of strength. Ann Oncol 2008;19(2):212–22. strategies, such as prefilled boxes or foiled-blister packs can [8] Banna GL, Collovà E, Gebbia V, et al. Anticancer oral therapy: emerging related enhance treatment adherence [57,58] and treatment outcomes issues. Cancer Treat Rev 2010;36:595–605. [9] Bhattacharyya GS. Oral systemic therapy: not all ‘‘win-win”. Indian J Med [59]. These may be used to complement the evolving technological Paediatr Oncol 2010;31(1):1–3. methods, such as audio-visual or text messaging, electronic mail [10] NCCN. National comprehensive cancer network. Breast Cancer version and other automated alert systems [56,57]. Integrated behavioural, 2016;1:2016. [11] Sabate E. Adherence to Long-Term Therapies: Evidence for Action. 20 Avenue motivational and educational interventions combined with peri- Appia, 1211 Geneva 27, Switzerland; 2003. odic telephone follow-ups and home visits seem to positively [12] Harvey RD, McKibbin T, Behera M, et al. Adherence reporting in phase III trials impact adherence in older patients post-hospital discharge of approved oral anticancer agents: a systematic review. J Clin Oncol (Meeting [60,61]. The Multinational Association for Supportive Care Abstracts) 2013;31(Suppl. 15):e20596. [13] Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: (MASCC) has developed a 4-section teaching tool for patients terminology and definitions. Value Health 2008;11(1):44–7. receiving OCA, the MASCC Oral Agent Teaching Tool (MOAT), [14] Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353 which includes (a) patient assessment of knowledge of the treat- (5):487–97. [15] Vrijens B, De Geest S, Hughes DA, et al. A new taxonomy for describing and ment plan, current medications, and ability to obtain and take an defining adherence to medications. Br J Clin Pharmacol 2012;73(5):691–705. oral therapy, (b) patient teaching instructions for storage, handling, [16] Raebel MA, Schmittdiel J, Karter AJ, et al. Standardizing terminology and and disposal, drug reminder system, and actions to take for various definitions of medication adherence and persistence in research employing electronic databases. Med Care 2013;51(8 Suppl. 3):S11–21. situations, (c) drug-specific information on dosing regimen, side- [17] Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self- effects, and potential interactions, and (d) questions to evaluate reported measure of medication adherence. Med Care 1986;24(1):67–74. understanding of the information provided [62]. [18] Morisky DE, Ang A, Krousel-Wood M, et al. Predictive validity of a medication adherence measure in an outpatient setting. J Clin Hypertension 2008;10 (5):348–54. [19] Verbrugghe M, Duprez V, Beeckman D, et al. Factors influencing adherence in Conclusion cancer patients taking oral tyrosine kinase inhibitors: a qualitative study. Cancer Nurs 2016;39(2):153–62. [20] Hughes CM. Medication non-adherence in the elderly: how big is the The best available treatment option based on efficacy and toler- problem? Drugs Aging 2004;21(12):793–811. ability should be offered to older adults with cancer. When OCA is [21] Kardas P, Lewek P, Matyjaszczyk M. Determinants of patient adherence: a an option, adherence should be closely monitored as this may be review of systematic reviews. Front Pharmacol 2013;4:91. [22] Brown MT, Bussell JK. Medication adherence: WHO cares? Mayo Clin Proc more easily compromised in older patients specifically in the pres- 2011;86(4):304–14. ence of relevant risk factors, such as cognitive impairment, multi- [23] Campbell NL, Boustani MA, Skopelja EN, Gao S, Unverzagt FW, Murray MD. morbidity, and polypharmacy. Use of OCA will only be effective if Medication adherence in older adults with cognitive impairment: a systematic evidence-based review. Am J Geriatr Pharmacother 2012;10(3):165–77. adherence is optimized. Barriers to adherence must be identified [24] Jankowska-Polanska B, Katarzyna L, Lidia A, et al. Cognitive function and and proactively managed in a multidisciplinary setting. Integrated adherence to anticoagulation treatment in patients with atrial fibrillation. J strategies are effective and must be implemented and personalized Geriatr Cardiol 2016;13(7):559–65. according to patient’s needs and availability of resources. Efforts [25] Klepin HD, Geiger AM, Bandos H, et al. Cognitive factors associated with adherence to oral antiestrogen therapy: results from the cognition in the study must be made to include assessment of adherence in future clinical of tamoxifen and raloxifene (Co-STAR) study. Cancer Prev Res (Phila) 2014;7 trials involving oral drugs. (1):161–8. [26] Sharma M, Loh KP, Nightingale G, et al. Polypharmacy and potentially inappropriate medication use in geriatric oncology. J Geriatr Oncol 2016;7 (5):346–53. Disclosures [27] Haynes RB, Ackloo E, Sahota N, et al. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2008;16(2):CD000011. The authors have declared no conflicts of interest. [28] Neugut AI, Zhong X, Wright JD, et al. Nonadherence to medications for chronic conditions and nonadherence to adjuvant hormonal therapy in women with breast cancer. JAMA Oncol 2016;2(10):1326–32. [29] Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and Funding pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol 2004;57(1):6–14. [30] Riechelmann RP, Zimmermann C, Chin SN, et al. Potential drug interactions in This research did not receive any specific grant from funding cancer patients receiving supportive care exclusively. J Pain Symptom Manage agencies in the public, commercial, or not-for-profit sectors. 2008;35(5):535–43. [31] Prithviraj GK, Koroukian S, Margevicius S, et al. Patient characteristics associated with polypharmacy and inappropriate prescribing of medications among older adults with cancer. J Geriatr Oncol 2012;3(3):228–37. Acknowledgement [32] Popa MA, Wallace KJ, Brunello A, et al. Potential drug interactions and chemotoxicity in older patients with cancer receiving chemotherapy. J Geriatr We acknowledge the SIOG internal reviewing committee Oncol 2014;5(3):307–14. [33] Segal EM, Flood MR, Mancini RS, et al. Oral chemotherapy food and drug (W. van de Water, C. Steer, and G.S. Bhattacharyya) for providing interactions: a comprehensive review of the literature. J Oncol Pract 2014;10 feedbacks on the manuscript. (4):e255–68.

[34] Bedard PL, Bernard-Marty C, Raimondi C, et al. The role of capecitabine in the [60] Mistiaen P, Francke AL, Poot E. Interventions aimed at reducing problems in management of breast cancer in elderly patients. J Geriatric Oncol 2011;2 adult patients discharged from hospital to home: a systematic meta-review. (1):72–81. BMC Health Serv Res 2007;7:47. [35] Henry NL, Azzouz F, Desta Z, et al. Predictors of aromatase inhibitor [61] Ouwens M, Wollersheim H, Hermens R, et al. Integrated care programmes for discontinuation as a result of treatment-emergent symptoms in early-stage chronically ill patients: a review of systematic reviews. Int J Qual Health Care breast cancer. J Clin Oncol: Off J Am Soc Clin Oncol 2012;30(9):936–42. 2005;17(2):141–6. [36] Lee HS, Lee JY, Ah YM, et al. Low adherence to upfront and extended adjuvant [62] Kav S, Schulmeister L, Nirenberg A, et al. Development of the MASCC teaching letrozole therapy among early breast cancer patients in a clinical practice tool for patients receiving oral agents for cancer. Support Care Cancer 2010;18 setting. Oncology 2014;86(5–6):340–9. (5):583–90. [37] Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, et al. [63] Brito C, Portela MC, de Vasconcellos MT. Adherence to hormone therapy Temozolomide chemotherapy alone versus radiotherapy alone for malignant among women with breast cancer. BMC Cancer 2014;14:397. astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet [64] Danilak M, Chambers CR. Adherence to adjuvant endocrine therapy in women Oncol 2012;13:707–15. with breast cancer. J Oncol Pharm Pract 2013;19(2):105–10. [38] Putz F, Knippen S, Lahmer G, et al. A model to predict the feasibility of [65] Fink AK, Gurwitz J, Rakowski W, et al. Patient beliefs and tamoxifen concurrent chemoradiotherapy with temozolomide in glioblastoma discontinuance in older women with estrogen receptor–positive breast multiforme patients over age 65. Am J Clin Oncol 2015. cancer. J Clin Oncol: Off J Am Soc Clin Oncol 2004;22(16):3309–15. [39] Jackman DM, Yeap BY, Lindeman NI, et al. Phase II clinical trial of [66] Font R, Espinas JA, Gil-Gil M, et al. Prescription refill, patient self-report and chemotherapy-naive patients > or = 70 years of age treated with erlotinib physician report in assessing adherence to oral endocrine therapy in early for advanced non-small-cell lung cancer. J Clin Oncol: Off J Am Soc Clin Oncol breast cancer patients: a retrospective cohort study in Catalonia, Spain. Br J 2007;25(7):760–6. Cancer 2012;107(8):1249–56. [40] Mayer EL, Partridge AH, Harris LN, et al. Tolerability of and adherence to [67] He W, Fang F, Varnum C, et al. Predictors of discontinuation of adjuvant combination oral therapy with gefitinib and capecitabine in metastatic breast hormone therapy in patients with breast cancer. J Clin Oncol: Off J Am Soc Clin cancer. Breast Cancer Res Treat 2009;117(3):615–23. Oncol 2015;33(20):2262–9. [41] Greer JA, Amoyal N, Nisotel L, et al. A systematic review of adherence to oral [68] Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence antineoplastic therapies. Oncologist 2016;21(3):354–76. to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer [42] Halpern R, Barghout V, Zarotsky V, Williams DE. Costs and utilization patients. J Clin Oncol: Off J Am Soc Clin Oncol 2010;28(27):4120–8. associated with imatinib adherence in patients with chronic myeloid [69] Hershman DL, Tsui J, Meyer J, et al. The change from brand-name to generic leukemia or gastrointestinal stromal tumors. JCOM 2009;16(5):217–23. aromatase inhibitors and hormone therapy adherence for early-stage breast [43] Hershman DL, Shao T, Kushi LH, et al. Early discontinuation and non- cancer. J Natl Cancer Inst 2014;106(11). adherence to adjuvant hormonal therapy are associated with increased [70] Hershman DL, Tsui J, Wright JD, et al. Household net worth, racial disparities, mortality in women with breast cancer. Breast Cancer Res Treat 2011;126 and hormonal therapy adherence among women with early-stage breast (2):529–37. cancer. J Clin Oncol: Off J Am Soc Clin Oncol 2015;33(9):1053–9. [44] Chirgwin JH, Giobbie-Hurder A, Coates AS, et al. Treatment adherence and its [71] Hsieh KP, Chen LC, Cheung KL, et al. Interruption and non-adherence to long- impact on disease-free survival in the breast international group 1–98 trial of term adjuvant hormone therapy is associated with adverse survival outcome tamoxifen and letrozole, alone and in sequence. J Clin Oncol: Off J Am Soc Clin of breast cancer women – an Asian population-based study. PLoS ONE 2014;9 Oncol 2016;34(21):2452–9. (2):e87027. [45] Ma AM, Barone J, Wallis AE, et al. Noncompliance with adjuvant radiation, [72] Hsieh KP, Chen LC, Cheung KL, et al. Risks of nonadherence to hormone chemotherapy, or hormonal therapy in breast cancer patients. Am J Surg therapy in Asian women with breast cancer. Kaohsiung J Med Sci 2015;31 2008;196(4):500–4. (6):328–34. [46] Xu S, Yang Y, Tao W, et al. Tamoxifen adherence and its relationship to [73] Neugut AI, Subar M, Wilde ET, et al. Association between prescription co- mortality in 116 men with breast cancer. Breast Cancer Res Treat 2012;136 payment amount and compliance with adjuvant hormonal therapy in women (2):495–502. with early-stage breast cancer. J Clin Oncol: Off J Am Soc Clin Oncol 2011;29 [47] Costa E, Giardini A, Savin M, et al. Interventional tools to improve medication (18):2534–42. adherence: review of literature. Patient Prefer Adherence 2015;9:1303–14. [74] Owusu C, Buist DS, Field TS, et al. Predictors of tamoxifen discontinuation [48] Network NCC. NCCN Clinical Practice Guidelines in Oncology. Senior Adult among older women with estrogen receptor-positive breast cancer. J Clin Oncology. Version 2.2016; 2016. Oncol: Off J Am Soc Clin Oncol 2008;26(4):549–55. [49] Zolnierek KB, Dimatteo MR. Physician communication and patient adherence [75] Trabulsi N, Riedel K, Winslade N, et al. Adherence to anti-estrogen therapy in to treatment: a meta-analysis. Med Care 2009;47(8):826–34. seniors with breast cancer: how well are we doing? Breast J 2014;20(6):632–8. [50] Burstein HJ, Temin S, Anderson H, et al. Adjuvant endocrine therapy for [76] Partridge AH, Archer L, Kornblith AB, et al. Adherence and persistence with women with hormone receptor-positive breast cancer: American society of oral adjuvant chemotherapy in older women with early-stage breast cancer in clinical oncology clinical practice guideline focused update. J Clin Oncol: Off J CALGB 49907: adherence companion study 60104. J Clin Oncol: Off J Am Soc Am Soc Clin Oncol 2014;32(21):2255–69. Clin Oncol 2010;28(14):2418–22. [51] Neuner JM, Kamaraju S, Charlson JA, et al. The introduction of generic [77] Figueiredo Junior AGD, Forones NM. Study on adherence to capecitabine aromatase inhibitors and treatment adherence among Medicare D enrollees. J among patients with colorectal cancer and metastatic breast cancer. Arq Natl Cancer Inst 2015;107(8). Gastroenterol 2014;51(3):186–91. [52] Panagioti M, Richardson G, Small N, et al. Self-management support [78] Winterhalder R, Hoesli P, Delmore G, et al. Self-reported compliance with interventions to reduce health care utilisation without compromising capecitabine: findings from a prospective cohort analysis. Oncology 2011;80 outcomes: a systematic review and meta-analysis. BMC Health Serv Res (1–2):29–33. 2014;14:356. [79] Seal BS, Anderson S, Shermock KM. Factors associated with adherence rates for [53] Viswanathan M, Golin CE, Jones CD, et al. Interventions to improve adherence oral and intravenous anticancer therapy in commercially insured patients with to self-administered medications for chronic diseases in the United States: a metastatic colon cancer. J Manage Care Spec Pharm 2016;22(3):227–35. systematic review. Ann Intern Med 2012;157(11):785–95. [80] Krolop L, Ko YD, Schwindt PF, et al. Adherence management for patients with [54] Stevenson FA, Cox K, Britten N, et al. A systematic review of the research on cancer taking capecitabine: a prospective two-arm cohort study. BMJ Open communication between patients and health care professionals about 2013;3(7). medicines: the consequences for concordance. Health Expect 2004;7 [81] Ruddy KJ, Pitcher BN, Archer LE, et al. Persistence, adherence, and toxicity with (3):235–45. oral CMF in older women with early-stage breast cancer (Adherence [55] Creel PA. Optimizing patient adherence to targeted therapies in renal cell Companion Study 60104 for CALGB 49907). Ann Oncol 2012;23(12):3075–81. carcinoma. Clin J Oncol Nursing 2014;18(6):694–700. 697p. [82] Timmers L, Boons CC, Moes-Ten Hove J, et al. Adherence, exposure and [56] Schneider SM, Hess K, Gosselin T. Interventions to promote adherence with patients’ experiences with the use of erlotinib in non-small cell lung cancer. J oral agents. Semin Oncol Nurs 2011;27(2):133–41. Cancer Res Clin Oncol 2015;141(8):1481–91. [57] Dupclay L, Eaddy M, Jackson J, et al. Real-world impact of reminder packaging [83] Lafeuille MH, Grittner AM, Lefebvre P, Ellis L, McKenzie S, Slaton T, Kozma C. on antihypertensive treatment adherence and persistence. Patient Prefer Adherence Patterns for Abiraterone Acetate and Concomitant Prednisone Use Adherence 2012;6:499–507. in Patients with Prostate Cancer. J Manage Care Spec Pharm 2014;20 [58] Boeni F, Spinatsch E, Suter K, et al. Effect of drug reminder packaging on (5):477–84. medication adherence: a systematic review revealing research gaps. Syst Rev [84] Grundmark B, Garmo H, Zethelius B, et al. Anti-androgen prescribing patterns, 2014;3:29. patient treatment adherence and influencing factors; results from the [59] Schneider PJ, Murphy JE and Pedersen CA. Impact of medication packaging on nationwide PCBaSe Sweden. Eur J Clin Pharmacol 2012;68(12):1619–30. adherence and treatment outcomes in older ambulatory patients. J Am Pharm Assoc (2003). 2008; 48(1):58–63.