Geriatric Nursing 35 (2014) S49eS56

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Feature Article

Surviving with lung cancer: Medication-taking and oral targeted therapy Karen E. Wickersham, PhD, RN a, d, *, Mary Beth Happ, PhD, RN, FAAN a, c, Catherine M. Bender, PhD, RN, FAAN a, Sandra J. Engberg, PhD, CRNP, RN, FAAN a, Ahmad Tarhini, MD, PhD, MSc b, Judith A. Erlen, PhD, RN, FAAN a a

University of Pittsburgh School of Nursing, USA University of Pittsburgh School of Medicine, USA c The Ohio State University College of Nursing, USA d University of Maryland, Baltimore, School of Nursing, USA b

a b s t r a c t Keywords: Medication-taking Grounded theory Non-small cell lung cancer Erlotinib Epidermal growth factor receptor

Oral epidermal growth factor receptor inhibitors (EGFRIs) improve survival for non-small cell lung cancer (NSCLC) patients; however, medication-taking implications are unknown. We used grounded theory to explore the process of medication-taking for NSCLC patients receiving oral EGFRIs. Thirty-two interviews were conducted for 13 participants purposively selected for gender, race/ethnicity, age, time in therapy, dose reductions, and therapy discontinuation and theoretically sampled for age and health insurance carrier. The study produced a grounded theory, Surviving with Lung Cancer, in which participants framed EGFRI therapy within recognition of NSCLC as a life-limiting illness without cure. Medication-taking was a “window” into participants’ process of surviving with metastatic cancer that included deciding and preparing to take EGFRIs and treating lung cancer as a chronic condition. Our results contribute to understanding how NSCLC patients view themselves in the context of a life-limiting illness and support development of a theoretically-based intervention to improve medication-taking with EGFRIs. Ó 2014 Mosby, Inc. All rights reserved.

Introduction Lung cancer is the leading cause of cancer deaths in the US for both men and women, with 159,480 deaths estimated for 2013.1 Non-small cell lung cancer (NSCLC) comprises approximately 85% of lung cancer cases and occurs in both smokers and nonsmokers.2 NSCLC adenocarcinoma is largely a disease of older adults.3e6 The mean age at diagnosis is 71 years of age. Lung cancer represents a major disease burden in older adults7; overall, approximately 70% of patients with NSCLC are diagnosed at an advanced stage (stage III/IV), are over 65 years of age at the time of diagnosis, and have a 15.6% five-year relative survival rate.1,5

Funding: Funding was provided through a National Institute of Nursing Research, National Research Service Award (F31NR011261); “Technology: Research in Chronic and Critical Illness” T32 Training Grant (T32 NR008857); Bessie Li Sze Scholarship Award for Graduate Students in Oncology; The University of Virginia School of Nursing Alumni Association Scholarship; Sigma Theta Tau International, Eta Chapter Research Award; and the American Cancer Society Doctoral Degree Scholarship in Cancer Nursing (DSCN-11-193-01). Conflict of interest: No conflict of interest has been declared by the authors. * Corresponding author. University of Maryland, Baltimore, School of Nursing, RM 731A, 655 West Lombard Street, Baltimore, MD 21201, USA. Tel.: þ1 410 706 5119. E-mail address: [email protected] (K.E. Wickersham). 0197-4572/$ e see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.gerinurse.2014.02.020

The approach to NSCLC treatment has shifted to increased use of oral targeted therapies.8 For NSCLC patients, targeted therapy development has focused on the epidermal growth factor receptor (EGFR). Oral EGFR inhibitors (EGFRIs), such as erlotinib (TarcevaÒ, OSI Pharmaceuticals, Farmingdale, NY), play a key role in management of advanced stage NSCLC. Generally, oral EGFRIs for advanced NSCLC are taken daily until they become ineffective (weeks to years), unlike oral chemotherapy (e.g., capecitabine) or hormonal therapy (e.g., anastrozole). Medication-taking of oral EGFRIs, which includes activities such as identifying and counting pills, timing pill taking with meals, and refilling prescriptions,9 is crucial for prolonging survival for persons with NSCLC; however, individuals aged 70 years and older face unique challenges that may influence medication-taking behaviors related to oral EGFRI therapy, such as negotiating the effects of multiple co-morbidities,10e12 managing complicated medication regimens,13 suffering from functional and cognitive declines and experiencing depressive symptomatology.14,15 Unfortunately, there is little research to guide our understanding of the medication-taking process or the meaning of medication-taking for adults receiving oral EGFRI therapy. Therefore, the purpose of this grounded theory study was to explore the process of medication-taking for adults with NSCLC taking oral EGFRIs.

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Traditionally, NSCLC has been treated with surgery, chemotherapy, and/or radiation therapy (Table 1); however, recent advances in understanding genetic mutations in cancer16 have led to development of new drugs to target these mutations and improve survival. For persons with NSCLC, tyrosine kinase inhibitors that disrupt function of the EGFR improve survival and quality of life.17,18 The oral EGFRI approved for use for NSCLC treatment at the time we conducted our study was erlotinib, which is now approved for: (1) first-line therapy for patients with metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations19,20; (2) treatment of refractory NSCLC (2nd, 3rd line therapy) of nonsquamous and squamous histology,18 where it is most widely used; and (3) maintenance therapy after 1st line platinum-based chemotherapy in persons who achieve stable disease or response.21 Medication-taking and erlotinib Erlotinib is less toxic and more convenient for patients to take compared to standard chemotherapy; however, the side effect profile of erlotinib is unique to the pathway it inhibits. Common side effects of erlotinib include rash, diarrhea, fatigue, and anorexia.22 The effect of the experience of medication-taking with erlotinib, including impact of side effects on medication-taking behaviors, for persons with NSCLC is not understood. Qualitative inquiry provides unique information about medication-taking behaviors and experiences of patients with chronic disorders.23e26 Most qualitative studies of medication-taking of patients with cancer are focused on developmental issues such as egocentrism, concrete thinking, and parental involvement among children or adolescents.25,27 Understanding the process of medication-taking for adults with NSCLC taking oral EGFRI therapy is necessary to provide comprehensive patient-centered care and to develop and test interventions tailored to the needs of persons with NSCLC. The study Aim We explored the process of medication-taking for adults with NSCLC receiving oral EGFRI therapy. Our goal was to develop a Table 1 Treatment of non-small cell lung cancer by stage of disease. TNM stage

Treatment

Occult carcinoma 0 IA IB IIA

Observation

IIB IIIA IIIB IV

Observation If operable, surgical resection  observation/SABR If operable, surgical resection  observation/SABR/chemotherapy If operable, surgical resection  observation/SABR/ chemotherapy/chemoradiation If operable, surgical resection  observation/SABR/ chemotherapy/chemoradiation Chemotherapy or concurrent chemoradiation Concurrent chemoradiation If mutation D ¼ erlotinib, afatanib (EGFRþ) or crizotinib (EML4 rearrangement þ) If mutation L and PS 0e1 ¼  Doublet chemotherapy  Chemotherapy þ bevacizumab  Cisplatin/pemetrexed  Cetuximab/vinorelbine/pemetrexed If mutation  and PS 2 ¼ chemotherapy If mutation  and PS 3 ¼ best supportive care

SABR ¼ stereotactic ablative radiotherapy; T ¼ primary tumor; N ¼ regional lymph node involvement; M ¼ metastases; PS ¼ performance status; EGFR ¼ epidermal growth factor receptor; EML4 ¼ echinoderm microtubule-associated protein-like 4. Adapted from Lababede et al (2011).

grounded theory that described and explained the process of medication-taking for adults in this patient population. Design We used grounded theory for the purpose of constructing, testing, and refining theory from data.28,29 The underlying assumption of grounded theory is that groups of individuals share a distinct psychosocial problem that is resolved through a process.28 Setting and sample Our university Institutional Review Board approved this study. Informed consent was obtained from all participants prior to data collection. Participants were individuals treated for NSCLC at two outpatient lung cancer clinics at a National Cancer Institutedesignated cancer center. The principal investigator (PI; KW) was not part of the clinical care team and used clinic observations and chart reviews to screen eligible patients and to understand the participant’s treatment trajectory. Members of the clinical team (i.e., an oncologist, a nurse practitioner, physician’s assistant, or a collaborative nurse) identified and approached potential participants to assess their interest in study participation. The PI met with interested patients in a private area at the recruitment sites or discussed the study by phone. Participants Men and women over 21 years of age with NSCLC (any type/ stage) receiving an oral EGFRI and able to speak, read, and understand English were eligible for the study. Exclusion criteria included a primary cancer that had metastasized to the lung or a second primary cancer, current metastasis to the central nervous system, or evidence of cognitive impairment as assessed by Mini-Mental Status Exam (MMSE)30 scores at or below the borderline range (1.4 SD below age- and education-scaled norm).31 Participants were purposively selected for variation in gender, race/ethnicity, age, time in therapy, reductions in dose of their EGFRI, and therapy discontinuation.32 Twenty patients expressed interest in the study; one was excluded for a second primary cancer and six did not enroll (e.g., “too much going on,” disclosure concerns, declining performance status). None were excluded due to cognitive dysfunction. Data collection: interviews Data were collected from August 2011 to August 2012. The PI conducted digitally recorded, in-depth, semi-formal interviews (n ¼ 27) with 13 participants and five brief telephone interviews for follow-up using an interview guide with questions about EGFRI medication-taking behaviors (Table 2).24,33,34 Interviews ranged from 32 to 90 min and were conducted in the participant’s home or at a convenient location that afforded privacy for the participant. Most (n ¼ 10) were interviewed on multiple occasions to capture the medication-taking process in early, middle, and later phases of erlotinib use. The (two) recorders failed for one interview, which was reconstructed immediately. Participants received $10 after each interview. As data collection and analysis progressed, we added questions about treatment delays, support groups for persons receiving oral EGFRIs, prescription medication insurance coverage, and disclosure of NSCLC and/or EGFRI use to family or friends. Supplemental data sources included an erlotinib starter kit, lay cancer journals, prescription package inserts, and personal documents (e.g., transcript of a speech) given to the PI by the participants or the clinical team.

K.E. Wickersham et al. / Geriatric Nursing 35 (2014) S49eS56 Table 2 Sample interview guide. Grand tour question

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Table 3 Participants’ sociodemographic-, illness-, and treatment-related characteristics. Probes

What is it like for you to take that medication?  Why/when/how did you start?  How does it make you feel?  What were you told?  How is it different from previous treatment? Tell me how you take erlotinib on a typical day.  What kind of strategies do you use to help you?  How do you decide when to take them? What do you find difficult?  What would be your “deal breaker?” Patients sometimes miss doses or find it difficult  What happens when you to take at the same time each day. How is that miss a dose? for you?  What happens when a dose is late? Some people don’t realize that they forget doses.  Were there unexpected, Does that ever happen for you? non-routine things?  What were you told to do if you missed a dose? Do you experience any side effects that interfere  How do you manage them? with taking your medicine? Who is helpful to you in taking erlotinib?  In what ways does he/she help?  How have health care providers helped you?

The contributions of a spouse or support person present during the interview at the person’s request/agreement were included in the analysis. Data analysis We used descriptive statistics to characterize the sample. The primary analytic approach was constant comparative analysis.29 Each transcript was reviewed while listening to the recording to assure accuracy and to gain an impression of the participant’s focus. In an iterative fashion, transcribed data were examined line-by-line to label (open code) text that related to participants’ medicationtaking of oral EGFRIs. Similar codes were grouped into categories. We then examined the relationships between categories of codes (axial coding) among the participants. Selective coding was used to identify and systematically connect the core category with other categories.29 ATLAS.ti (6.2.27) (Scientific Software Development GmbH, Berlin, Germany) software was used for data management. Consistent with Corbin and Strauss29 grounded theory, other analytic techniques included questioning the data, dimensional analysis, matrix construction, writing case titles and story summaries, and a literature review. Sampling, interviewing, and analysis continued until we reached informational redundancy (i.e., no new themes were recognized; n ¼ 8 participants). We then enrolled three participants to confirm existing findings. Based on the evolving theory (theoretical sampling), one woman and one man were selected for health insurance carrier, because health insurance and cost were concerns frequently expressed by the participants. One man was selected for younger age because aging and end of life were recurring themes in participants’ interviews. We achieved theoretical saturation after interviewing 13 participants.

Characteristic Age (in years) Mean (range) Years of education Mean (range) Marital status, n (%) Married Never married Widowed Ethnicity, n (%) White African American Asian Gender, n (%) Male Female Health care insurance coverage, n (%) Managed Medicare Commercial insurance COBRA Stage at diagnosis, n (%) II/IIa IIIb/IV Duration of therapy with EGFR inhibitor Reductions in dose of EGFR inhibitor therapy Discontinued therapy with EGFR inhibitor

Participants (N ¼ 13) 70.5 (52e83) 14.6 (11e22) 9 (69.2) 1 (7.7) 3 (23.1) 11 (84.6) 1 (7.7) 1 (7.7) 5 (38.5) 8 (61.5) 8 (61.5) 4 (30.8) 1 (7.7) 2 (15.4) 11 (84.6) 1 week to 6 years 5 (38.5) 2 (15.4)

COBRA ¼ Consolidated Omnibus Budget Reconciliation Act health insurance; EGFR ¼ epidermal growth factor receptor.

conducted as follows: 1) Three key informants were selected to review and comment on the constructed theory to confirm or refine the interpretive analysis. We provided a summary of the findings in lay language with quotations to the informants for their review. All three confirmed the conceptual model. 2) Review of public websites (e.g., Cancer Grace, Inspire.com) provided external validation of the psychosocial process. 3) We reviewed and coded a publicly available interview transcript of an opera singer who takes erlotinib. 4) Findings were shared with the cancer center clinicians and nursing staff who also confirmed study findings. Findings The participants The final sample (N ¼ 13) consisted of five men (38.5%) and eight women (61.5%) (Table 3). The mean age of the participants was 70.5 years, and the range was 52e83 years of age. All participants took erlotinib as their oral EGFRI therapy. Six participants (46.2%) had a documented mutation of the EGFR gene. Participants had been taking erlotinib for one week to six or more years; two participants took erlotinib as part of a clinical trial but the cost of therapy was covered by their health insurance. Four participants were well established in their therapy (e.g., about 1 year into treatment) and nine participants were either in an early phase of treatment (e.g., first week to two months) or their process changed during the course of the study (e.g., stopped therapy due to disease progression). Three participants died during the study period. One woman declined further involvement after the first interview due to fatigue and “seeing too many doctors.” The grounded theory: Surviving with Lung Cancer

Rigor Rigor was accomplished through vigilant documentation, member checking, dual-coder review and discussion of all transcripts (KW, MBH), and audit trails.35 Member checking was

Our exploration of medication-taking with oral EGFRI therapy led to discovery of the theory of Surviving with Lung Cancer, which is framed within the context of participants’ recognition of NSCLC as a life-limiting illness without cure (Fig. 1). EGFRI therapy was a

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Deciding to take erlotinib therapy

necessary condition of the process, which was comprised of three dynamic phases: a) deciding to take EGFRI therapy, b) preparing for EGFRI therapy, and c) treating lung cancer as a chronic condition. Some participants “survived” for a period of time on other therapies, while for others survival began with oral EGFRI therapy. All participants were acutely aware that they would not survive after lung cancer, but with it. Some described a realistic perception of the role of erlotinib in their survival, “Actually, TarcevaÒ is not a cure, it just stops the cancer from growing, that’s all.” Regardless of its purpose, some participants referred to erlotinib as “the miracle drug” meaning that “it worked (took effect) right away.” Others characterized their survival as an ongoing struggle between recognizing “what will be will be” and continuing to hope for a miracle (i.e., cure). Most (10/13) participants prioritized the meaning of erlotinib in the context of their survival, “If you care and you want to survive this cancer, then you do it.” The length of time one survived with lung cancer varied (e.g., weeks to years) and the meaning of surviving with a chronic terminal illness differed among participants (“Just a challenge to see how long I can live” versus “getting back into the mainstream”), but the process of surviving with lung cancer was similar for all.

Participants took erlotinib because of an identified or presumed genetic mutation, framing this genetic compatibility as “what works best with my NSCLC.” Most were aware of their mutation status and some specifically sought erlotinib because of it. A daughter described:

. If I stop the drug the tumors can grow back, so you either take it and deal with any side effects or little inconveniences like having to wear solar protective clothing. being faithful to taking the medicine, or you throw in the towel, give up and say, “What will be will be,” and I’m not going there.

I had read a lot on their [a cancer website] about TarcevaÒ and the EGFR mutation. which is why we asked to test him for it because I tested positive for it e and I guess generally they won’t test somebody at his age group [80s] e but because there was a family history they tested. And he did test positive.

All participants described a decision-making process for choosing erlotinib therapy. Some took erlotinib on “doctor’s orders,” motivated by faith in their oncologist, “I decided a long time ago to put my faith in Dr. (oncologist). And when he said, ‘this is what I think you should do,’ that’s what I did.” Other participants initiated treatment based on the combined advice of their clinical team, family, and/or friends. Unacceptable toxicities or failure of other therapies were also conditions for starting erlotinib; for example, a woman took erlotinib after seven other therapies: I was able to tolerate it (chemotherapy) but. he (oncologist) said I can’t stay on it forever. he said to switch to the TarcevaÒ because I was starting to get numbness (from chemotherapy). just a little bit but he said it’s irreversible if it gets too bad.

Fig. 1. Basic psychosocial process. Circles: main themes. Squares: components of each theme (main tasks, process of each main theme). Double arrow line: represents that while these three phases overlap, they occur on a continuum. There is a beginning and an end to targeted therapy, but with multiple overlapping (or repeating steps) along the way. Dotted lines: represent decision points in the process. Diamonds: represent the decisions that were made by the participants. Dimensions of the process (gray circles): constructs that crosscut each phase. HCP ¼ health care professional (includes oncologists, thoracic surgeons, radiation oncologists, psychiatrist, radiation therapists, infusion nurses, nurses, collaborative nurses, nurse practitioner, physician’s assistant, clinical research coordinator, pharmacists, visiting nurse, or other health care providers that take part in the participant’s care).

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A man who took erlotinib for over two years summarized his decision-making process: I told my doctor. if he couldn’t improve on the first two experiences [chemotherapy], then I wanted to switch over to TarcevaÒ. And I came in with the knowledge about my cousin. had been on TarcevaÒ for three years. the median longevity the doctor said was 11 months. so I was encouraged because its effectiveness kind of varied according to genotype. indeed I had a good match with the drug.

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was not always apparent to the clinical team (“I don’t think that they [doctors] realize. he probably thought that I went to the pharmacy and got it”). Not meeting the assistance criteria and increasing drug prices added additional challenges for the participants. Furthermore, taking two strengths of erlotinib required two co-payments, adding an additional expense. In one case, the copayment influenced the dose that was acceptable to the patient, “. You pay for 100 (mg), and then 25 (mg), they’re two prescriptions. There’s two co-payments there. So it costs a lot more. if I go back to 150 (mg) then it’s just one co-payment.”

Preparing for erlotinib This phase referred to the tasks necessary for obtaining and managing erlotinib (e.g., “preliminary work”). It’s concerning. there’s so much preliminary that goes: first of all securing it. and then when you get it and read the directions, it’s “keep it at certain temperature,” and “wash your hands after taking the pill,” which I have never heard of before. Just in preparing and getting the pill. there is enough to let you know that this is something beyond an aspirin. This man’s description demonstrates that the preparing phase alerts patients to the importance and potency of erlotinib. This phase also included finding a specialty pharmacy, securing erlotinib through mail order, and deciphering the directions for taking it, such as, “avoid grapefruit juice.” The participants obtained information about what erlotinib does, how to take it, and how to get it from brochures, books, and/ or an erlotinib starter kit. Some deliberately avoided searching the Internet for information because “sometimes, not knowing is better.” Others selectively searched the Internet, “I [only] go there (American Cancer Society) or I look in the (cancer center). because I think there’s a lot of false information out there.” Paying for erlotinib was the primary focus of the preparing phase. Nearly all referred to the high cost, “It’s expensive. I want them to know that.” Many felt the cost of erlotinib was prohibitive. A woman who stopped taking erlotinib due to expensive copayments affirmed: Most patients figure it’s not worth it if you’re dying, you have cancer. Some would like to live but where’s the funds for you to survive? You can’t. They’ll break you, I tell you, this medication will break you. if you have to pay for it without insurance. It will break you in no time. In no time. Even if you pay with insurance, it’s (the cost) still high. In a subsequent interview, the same woman questioned the benefit of survival versus the cost of long-term erlotinib therapy, “I mean just to stay alive to pay for this drug, I don’t know.” Four participants received financial assistance either to pay for erlotinib or to defray the cost of prescription co-payments, but several struggled to obtain financial assistance, “. the first time, the insurance kept denying it. And my son. works for Medicare. he’s the one that suggested, ‘Write a letter to the foundation’. they can only say no.” A daughter described her experience in obtaining funds for her father’s medication: They (health insurance company) decided they would cover 10% of it. Well 10% of $5000 is [leaves] a lot of money every month [to pay]. I talked with [foundation oncologist]. once they got that paperwork and approved that yes, he did need the medication, and agreed that yes, he could take it first-line. literally within days they called, “Ok, your dad’s been approved”. “alright, what’s his co-pay?” “Zero.” And I was, “Are you kidding me?” Securing payment assistance approval for erlotinib resulted in a treatment delay (“So I got on the pill about 30 days later”), one that

Treating lung cancer as a chronic condition Advancing to treating lung cancer as “a chronic condition” followed the deciding and preparing phases. This phase represented the day-to-day challenges participants experienced in taking erlotinib and involved their recognition of the need for chronic EGFRI therapy (“We need to see where this drug will take me and it’ll give me a break from [chemotherapy].” “I don’t think that TarcevaÒ will totally eradicate my lung cancer. but it’s. making things not grow”). Treating NSCLC as a chronic condition included recognition of his/her ownership of the medication-taking process, “So I want to make sure that it’s effective by following. the directions and. if it says to take it the same time every day, I want to be sure that I take it the same time every day.” The mechanics of taking erlotinib often included comparison to another daily medication, such as, “My iron tablet was worse, so I haven’t been taking those, but no, I haven’t really had too much of an adjustment.” All participants described routinization or a habitual practice of taking erlotinib, “It’s a matter of discipline.” Routinization was associated with timing erlotinib with meals (e.g., 2 h before breakfast), a location (e.g., bedside table), time of day (e.g., AM or PM), and/or a storage strategy (e.g., pill minder). Routinization also involved the use of an alarm or other reminder (e.g., cats awaken a woman), visual aid (e.g., clear glass on a table filled with medication), or an active cue (e.g., moving pill bottles from front to back of a table) to take erlotinib. The women in the study who lived alone used a calendar or a steno pad to track doses of erlotinib, while participants who lived with a spouse relied on storage strategies as means of a “checks and balances” system for remembering to take erlotinib. One woman admitted to occasionally missing a dose (“I’m human, I miss some days”); however, most stated they never had difficulty remembering to take erlotinib because they associated it with a storage strategy and a location (“it’s all in that little glass that I put on the kitchen counter, so there’s no questioning later on”), time of day (“it is the first thing that I do in the morning”), or a proactive refilling strategy. Men often indicated they never forgot to take erlotinib because their wives prepared or gave it to them, so “there’s no question that the transaction takes place.” Participants recognized a need for “having help” in surviving with lung cancer. They found support from family, friends, Internet blogs, and/or pets. Family/social support included assistance with taking medication, active participation in special family connections, and being involved in the present. Enjoyment of family time served as further motivation for taking erlotinib daily (e.g., to see a grandson play baseball). The participant’s and the family’s prior experiences with cancer (e.g., spouse or parent who died from cancer) colored how they interacted with each other during the process of surviving with lung cancer; in particular, participants with genetic mutations shared a perceived survival obligation to family members, friends, prior research participants, and/or to those who have died.

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. my brothers want me to survive this cancer, I guess maybe if I can survive this long, they want me to survive a little longer. and I shouldn’t let them down. Erlotinib has unique side effects related to inhibition of the EGFR pathway. All participants experienced and recognized side effects as a part of managing NSCLC. The most commonly reported side effects were rash, diarrhea, stomach cramping/gastrointestinal upset, nail issues (e.g., nail splitting), eye itching, long eyelashes (“it looked like spider legs, it was wild”), and hair changes. Rash and diarrhea were referred to as “social inhibitors” and especially stigmatizing if one was working full-time: The biggest thing is you become. a little self-conscious because you know your face is all splotchy or red, and although I’ve seen some of the pictures where it’s very severe e thank God I haven’t gotten to that point, but it’s a little bit of a pain. I don’t want people looking at me, so it’s almost like I cover it (rash) up because it’s just treat me like I’m the same old person and not “Hey, there’s a cancer guy.” Five participants had dose reductions in their EGFRI due to side effect severity: I reached a point about two months into it where everything was changing. I noticed things burned when I ate, everything was hot to me, in my mouth, spicy hot. I said, “I can’t take this drug, I can’t eat. Everything is hot to me in my mouth. And (oncologist) said, “No, no, no, no, no, you’re doing so good. We’ll lower the dose, we’ll put you on 100 mg dose.” I said, “OK, I’m willing.” Despite the severity of side effects, participants expressed commitment to taking erlotinib, “You know if it’s keeping me alive, I’ll accept it.” While some admitted to skipping a dose when experiencing a distressing side effect, others perceived the rash as a hallmark for the effectiveness of erlotinib, “. I feel like because I have the side effects it must be working.” Surviving with lung cancer included rigorous self-assessment, self-maintenance, and external assessments required of one with advanced cancer. All participants discussed the role of exercise (e.g., swimming, Jazzercise), nutrition, routine health screenings (e.g., mammograms), prevention of EGFRI-related side effects (e.g., sun protective clothing, lotion without alcohol), and self-examination for new or worsening side effects as crucial activities for surviving with lung cancer. Periodic reassessments of lung cancer could prompt an increase in the dose of erlotinib, no change in dose, or discontinuation of therapy. Participants discussed the importance of “keeping busy” and “staying active” as a means of engaging the body and mind in their survival, particularly the older participants, “I’ve been really busy. I’m always busy. I like to be busy. I don’t want to sit around.” If you have a lot of exercise, you don’t feel the effects of the drug so much. But if you don’t exercise, you feel it all the time. you can’t take your mind off of it. And I think it’s partly psychological. I don’t feel good, I pack my swim bag and I go out. If I don’t feel good at the swimming pool. I go out for a walk. You find something other than your own illness to look at. Paying for erlotinib continued to be problematic during this third phase of the medication-taking process. Some became extremely aware of the cost associated with each pill, “Ok, I’m going to stick this in my mouth and this is $200, and I don’t want to waste it.” In an extreme case, a survivor stopped taking erlotinib due to co-payments that had increased from $60 to $600 over a 6-year period for a 90-day 100 mg prescription. Discontinuing erlotinib due to cost can be heartbreaking because the medication “gives you hope” and terminating therapy “takes that hope away.”

After a woman mentioned the need for support groups for persons who take erlotinib as a means for sharing experiences, we added a question about peer support groups to the interview guide. Subsequent participants agreed, “That’s the truth. I wish I had had someone to talk to.” I definitely think it would have. no information has ever been given to us regarding small groups for lung cancer, lung cancer families, or TarcevaÒ-taking patients. All of that would have been helpful. I don’t think there is a lot of that out there.

Dimensions of the process As analysis progressed it became obvious that several dimensions of the grounded theory crosscut all phases, particularly advocacy and the related negotiation required when weighing the benefits versus the risks of erlotinib therapy. Negotiation by the participant, a family member, or a clinician on behalf of the participant was apparent in every phase of the medication-taking process. Advocacy occurred on a continuum ranging from a mutual activity between a participant and a clinician to a participant being more directive, “You have to be very active in your own care.” I just asked him [oncologist] to lower it [dose of erlotinib]. I said I “don’t feel comfortable with it”. I didn’t know what was bothering me, but something was bothering me. So I told him to lower it. Persistent uncertainty due to the inability to distinguish side effects of erlotinib from symptoms of lung cancer or another process (e.g., aging) resulted in a desire to live life to the fullest because “you never know when your ship’s going down.” Participants discussed yearning for “quality of life, not quantity” or “feeling normal.” Family was central for these survivors who described prioritizing family time and planning exotic family vacations. Discussion The development of cancer therapies that target a specific gene or genetic mutation has led to increased survival for individuals with NSCLC; however, the personal and social ramifications of chronic oral targeted therapy have not been well defined. Our purpose was to generate a grounded theory that explained the process of medication-taking for adults with advanced stage NSCLC taking chronic treatment with an oral EGFRI. “Surviving with lung cancer” is the theory that explained the multidimensional, psychosocial, medication-taking process for NSCLC patients taking erlotinib. Medication-taking provided a “window” into the larger process of surviving with NCSLC within which medication-taking was a central and essential function. Our findings are unique in that they illustrate the active participation and sacrifice persons with NSCLC endured while taking erlotinib and help us to identify specific areas for potential intervention, such as side effect severity. The findings of our study contribute to the theoretical understanding of medication-taking in several ways. First, “surviving with lung cancer” elucidates the impact that chronic active treatment with oral targeted therapy has on cancer survivorship. Our participants were highly aware of the meaning of erlotinib, its active role in their daily survival, and the inevitable uncertainty surrounding the cause of treatment side effects or cancer symptoms, paying for erlotinib, and cancer treatment failure. Our participants recognized that they were not cancer survivors in the traditional sense36,37; rather, they took active treatment for a chronic life-threatening condition. They managed issues consistent with other chronically ill patient populations, such as individuals

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with cancer receiving trastuzumab,37 an intravenous therapy that targets a member of the EGFR family (HER2), persons with human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS) receiving chronic antiretroviral therapy,38,39 and older adults with heart disease23 or early stage dementia.40,41 Our previous study of medication-taking among women with earlystage breast cancer receiving therapy with an aromatase inhibitor, anastrozole, revealed that value/importance of medication, side effect severity, and medication self-management were primary constructs in the early phase of breast cancer survivorship.34 These constructs are amplified in the case of adults with metastatic NSCLC for whom procuring erlotinib, sustaining erlotinib therapy for weeks to years, managing side effects, and spending time with family were key components to surviving with lung cancer. Second, the findings add to the body of knowledge concerning aging adults who are taking a chronic therapy that will not cure but extend life for one with a terminal disease. Our findings were similar to Kagan’s42 study of older adults who coped with cancer by “integrating cancer into a life mostly lived”42(p.43) and to studies of older adults with early stage dementia,43 who also strived to integrate a terminal condition into their daily lives. Our participants were clearly focused on living with, managing, and integrating cancer into their daily lives. Third, the participants identified conditions (e.g., cost, side effect severity) under which older adults with NSCLC struggle to live with erlotinib therapy. These findings provide guidance for intervention development and add to existing knowledge by addressing the economic realities of older adults who are surviving with cancer. Finally, the participants’ narratives characterized the tension between knowing the limits of treatment for a condition unlikely to be cured and their own limits with taking that treatment (e.g., cost, side effect severity). As discussed by our participants, in many cases individuals have enough income to live (and therefore do not qualify for patient assistance programs) but not enough to cover prescription medication co-payments. Furthermore, prices of cancer therapies continue to surge upward; over the last decade, costs of cancer medications have doubled from an average of $5000 US per month to more than $10,000 US per month.44,45 Our older participants were keenly aware of increasing prices of medications, and their awareness of the cost of erlotinib raised an ethical question that one woman asked: is it worth it to live just to struggle to pay the increasing cost of chronic cancer treatment? Although we did not ask this question specifically, the narratives would indicate a resounding “yes” for most of the participants. Relishing family time was a key motivation for surviving with lung cancer by taking erlotinib therapy. In fact, family and social support went beyond medication assistance; rather, social support encompassed living in the moment and cherishing family time, such as an upcoming family vacation. Furthermore, family history influenced patients’ response to cancer and underscored: a) the importance of surviving for as long as possible for friends or family members who did not or could not survive themselves, and b) the hope for future cancer patients as we learn more about treatment and response with oral targeted therapy. Our findings should be interpreted in light of several limitations to the study. The sample was obtained from two clinics; however, they were within single cancer center. Purposive sampling to maximize variation of participants was used to minimize this limitation. Our participants were mostly older adults (aged 52 years or older), which is similar to patients with NSCLC nationally46; however, our sample included more women than men when compared to patients with NSCLC nationally47 and more participants with mutations of the EGFR gene.35e37 To address these potential limitations, the developing theory was shared with key participants and clinicians at the cancer center and at national

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conferences to understand and confirm the comparability and transferability of the findings; however, in hindsight, we may not have achieved full theoretical saturation in terms of the meaning of medication-taking for the participants in our sample. The most striking implications of this study are in the areas of affordable care and prescribing practices. High costs of medication and prescription co-payments were a source of concern for all participants. Several participants, specifically older women who lived alone, charged the PI with addressing this issue, which is relevant not only for patients with NSCLC, but also for patients with other types of cancer who take oral targeted therapies. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Survivorship48 state that cancer survivorship needs advancement in polices that address reimbursement and resource allocation issues. In addition, the Institute of Medicine’s report on cancer survivorship49 calls for interventions for consequences of cancer treatment (e.g., medication problems, symptoms, psychological distress, financial, and social concerns). Survivorship care plans for individuals with NSCLC that are developed by a health care team that includes nurses need to include a plan for affordable care and access to medication over time since insurance benefits may change or reach limits of coverage. Furthermore, we learned that patients manage two co-payments for dosages requiring two strengths of erlotinib (one co-pay for each strength). It is unclear whether the two co-payments are due to usual practice or pharmacist preference. Higher prescription co-payments have been associated with both nonpersistence and nonadherence to oral hormonal therapy for women over the age of 65 with early-stage breast cancer.50 Moreover, clinicians must be aware of potential delays in the start of treatment due to difficulty in securing access and payment. Clinicians must also reassess the patient’s access to medication over time as insurance benefits may change or reach limits. We present the participants’ stories of surviving with lung cancer, but the clinician perspective is an integral part of that story. Given the central role that clinicians play in assisting with procurement and maintenance of therapy and the suggestion from these data that clinicians may not be fully aware of cost and access to treatment problems, further studies of medication-taking that include the clinician perspective are needed. Generally, participants endorsed peer support groups for persons with NSCLC taking therapy with erlotinib. This finding suggests that support groups or group interventions based on select characteristics (e.g., gender, age, length of time in therapy) that address medication-taking and navigating concerns of survivorship are indicated for individuals with NSCLC. We sought to explore the process of medication-taking for persons with NSCLC receiving therapy with an oral EGFR inhibitor. We developed a substantive theory that explains the process of medication-taking as it relates to patient survival with NSCLC. Our results contribute to understanding how persons with NSCLC view themselves, the work they do to take an oral EGFR inhibitor, and their daily process of surviving with lung cancer, and provides support for a theoretically-based tailored intervention. Acknowledgments Preliminary results were presented at the University of Pittsburgh Cancer Institute Pre-Retreat Satellite Conference for the Biobehavioral Medicine in Oncology Program (June 2012) and the Oncology Nursing Society Connections: Advancing Care Through Science Conference (November 2012). We would like to acknowledge The University of Maryland Online Dissemination and Implementation Institute funded by the University of Maryland and the John A. Hartford Foundation and the support of the University

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of Pittsburgh Cancer Institute, especially Dr. David Friedland, Christopher Lindberg, Diane Gardner, Nancy Birus, and Darlene Landi. We extend special thanks to Dr. Jill Demirci, Jessica Devido, Melissa Knox, and Marissa Simon for their contributions to this project. Dr. M.B. Happ was a Professor and Dr. K.E. Wickersham a doctoral student at the University of Pittsburgh, School of Nursing at the time the study was conducted. Finally, we are most grateful to the participants of this study for their generosity and unwavering dedication to telling their stories. References 1. American Cancer Society (ACS). Cancer Facts and Figures. Available at: http:// www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-celllung-cancer-key-statistics. Accessed 17.04.13. 2. National Comprehensive Cancer Network (NCCN). Practice Guidelines in OncologyÔ: Non-small Cell Lung cancer. V2.2013. Available at: http://www. nccn.org/professionals/physician_gls/pdf/nscl.pdf; Accessed 16.07.13. 3. 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