Interventions to Improve Adherence and Symptoms for Oral Agents Sandra Spoelstra, PhD, MSN, RN Assistant Professor, Michigan State University College of Nursing Barbara A. Given, PhD, RN, FAAN (Co-PI) University Distinguished Professor and Associate Dean of Research Michigan State University College of Nursing Charles W. Given, PhD (Co-PI) Professor, Michigan State University College of Human Medicine, Department of Family Medicine Marcia Grant, DNSc, RN, FAAN (Co-PI) Director and Professor Nursing Research/Education, City of Hope Su Zie Ahn, MS Statistician, Michigan State University College of Nursing Oncology Nursing Society Research Conference February 11, 2011 Los Angeles, CA

Funding Source Supported by a research grant funded by the Oncology Nursing Society Foundation through an unrestricted grant from GlaxoSmithKline.

Conceptual Framework Patient Characteristics Socio-economic influences Education Age Sex Income Race/Ethnicity Health insurance Depressive symptoms Baseline/Intake Interview Regimen complexity (number per day * refills) Symptoms (side effects) Out-of-pocket cost to patient Beliefs about medications (BMQ) …………………………. Clinical Factors Disease & stage (solid cancer tumors) Symptom severity Treatment protocol characteristics (oral or oral + IV) AVR Interventions Information from AVR + Symptom Mgmt Toolkit +Monitoring adherence Reminders AVR Interventions + Nurse Intervention Symptom Mgmt and Adherence Monitoring Information Problem solving Assessment Reduction in Symptom Severity AVR Interventions + Nurse Intervention: Adherence Only Monitoring Information Problem solving Assessment Improved Adherence Acceptability Satisfaction w/ information Beliefs about Oral Agents RANDOMIZATIONRANDOMIZATION

Specific Aims Determine if the 3 arms of the trial differ on adherence outcome as measured by pills taken Determine if the 3 arms of the trial differ on symptom severity outcome (summed symptom severity of 15 symptoms) at the last contact and 10-weeks

Research Design Eligibility criteria: solid cancer tumors treatment with non-hormonal oral therapeutic agents. Obtained informed consent, enrolled & provided Symptom Management Toolkit (SMT). Intake Baseline Interview N = 119 Symptom severity, depression-CESD, belief s about oral agents & cost Randomization to 3-groups (based on cancer site, oral agent(s) & symptom severity. 37 men & 82 women, ages 28 to 86, and 76% Caucasian ARM-1 N = 40 Week 1 – 8 AVR calls symptom & adherence evaluation. ARM-2 N = 40 Week AVR calls symptom & adherence evaluation. ARM- 3 N = 39 Week AVR calls symptom & adherence evaluation. Week Nurse assessed & provided strategies for symptom management & adherence if any symptom was above threshold &/or adherence was < 80%. Week Nurse assessed & provided strategies for adherence only if adherence was < 80%. Exit 10-week Interview Symptom severity, depression-CESD, beliefs about oral agents & cost Follow-up Medical Record Audit & contacted specialty pharmacy for fill/refill information on oral agent(s). Patients satisfaction questionnaire.

Measures Symptom Experience Inventory Adherence with Oral Agent – Patient report – Medical record audit – Specialty pharmacy fill/refill CESD-20 Beliefs About Medications Out-of-Pocket Costs Satisfaction with Information and with Intervention Approach

Intervention Based on Cognitive Behavioral Therapy Baseline, 8 weekly contacts, and Exit Interview 1.AVR and referral to Symptom Toolkit for self care (no nurse involved) 2.AVR and brief Nurse* calls to focus on symptoms and adherence 3.AVR and brief Nurse* to focus only on strategies for adherence *Nurse involved only after week 4 when adherence under 80% or symptoms >4 for 2-consecutive weeks

Automated Voice Response System Patients were called at times of the day they preferred Responses via telephone key pad - touch tone Called 3 times over 40 minutes to try to reach Repeat next day if unavailable Finally, personal call if unable to reach

Tracking Patient Adherence Dosing information was loaded into data management software – number of pills, pills per day, weeks on/off Responses to weekly calls from automated voice response system compared to doses prescribed at intake

Managing Symptoms 1. Fatigue 2. Skin rash/skin sores 3. Lack of appetite 4. Distress 5. Constipation 6. Bodily pain 7. Diarrhea 8. Sores in mouth 9. Fever of ∧ or higher 10. Nausea or vomiting 11. Numbness or tingling 12. Shortness of breath 13. Sleep disturbance 14. Scaling of hands &feet 15. Pain/redness/peeling in hands and/or feet 15 common symptoms were assessed

Managing Symptoms If a symptom was rated as 4 or higher by a patient during the AVR call, they were referred to the Symptom Management Toolkit for self- management. If the symptom remained 4 or over 2- consecutive weeks the nurse conducted a brief call to refer the patients to the SMT and to follow the self-management techniques. The nurse followed up the next week to check on self-care, and continued calling until the symptom fell below 4.

Descriptive Statistics Mean age was 61.2 years of age (SD 13.7) 69% (N=82) Females & 31% (N=37) Males 76% (N=91) Caucasian, Asian 8% (N=9), African American 7% (N=8), other 8% (N=9) Married 67% (N=80), Widowed 14% (N=18), Never Married 10% (N=12) Education: – Some high school 26% (N=31) – Some college 32% (N=38) – Graduate school 42% (N=50)

Number of Patients by Type of Cancer

Oral Chemotherapy Agents N=119 Oral AgentsNumberPercent Capecitabine (Xeloda)4235% Erlotinib (Tarceva)2924% Lapatinib (Tykerb)119% Imatinib (Gleevec)98% Other98% Temozolomide (Temodar)76% Sunitinib (Sutent)65% Sorafenib (Nexavar)32.5% Methotrexate21.7% Cyclophosphamide (Cytoxin)10.8%

Adherence Group Distribution by Drug Cycle (Percent)

Complexity of Treatment Number of pills Number of times per day/days per week On/off days or weeks of meds (7 days on, 14 days off; 14 days on, then off; everyday; etc.) Over adhered patients had worse symptoms by week 10 (19 vs. 13)

Adherence by Drug Cycle Pattern N=10078% Adherence100% AdherenceOver Adhered 28 Days On (N=51) 51 (88)6 (10)1 (2) 14 Days On, 7 Days Off (N=25) 9 (36)4(16)12 (48) 7 Days On, 7 Days Off (N=9) 3 (33)- (-)6 (67) Other (N=8) 4 (50)3 (38)1 (13)

Missing 1-2 or 3 or More Doses n=57 n=25n=9n=8

Mean Symptom Severity Symptoms* Scores Overall N=119 Arm AVR Alone N=40 Arm 2 N=40 Arm 3 N=39 Intake20 (15)17 (12)19 (16)26 (17) Exit13 (13)11 (11)10 (9)17 (16) *18 th attritted +  28 (16)

Symptom Analyses Question: After adjusting for symptom severity at intake, did intervention group, and site of cancer affect symptom severity at 10 weeks? VariableEstimateSTD Error95% CIPr > Chi Sq Intercept <0.00 Baseline Symptom Severity <0.00 AVR Only AVR Plus Symptom Calls + Adherence Adherence Only---- Cancer Breast Lung Other----

Symptom Severity Analyses Question: What were the unadjusted means baseline to 10 weeks by arm? Was there a significant effect, over baseline? Arm Intake Exit (10 wks) Paired t-test p-value Mean St. Dev. Mean St. Dev. AVR Only AVR + Symptom Call + Adherence AVR + Adherence N=91

Symptom Severity Analyses by Site Question: What were the unadjusted means intake to 10 weeks by site? Cancer Site Intake Exit (10 Weeks) Paired t-test p-value MeanSt. Dev.Mean St. Dev. Breast Lung Other N=91

Model Linking Adherence Calls with Symptom Severity To determine how patient sex, cancer site, symptom severity at intake in three treatment groups, and adherence reports at IVR calls 1-8 were related to symptom severity scores at the 8 IVR contacts Site of cancer (breast, lung, other) did not affect symptom severity

Least Square Means for Symptom Severity Adjusted for Baseline Severity and Other Covariates Mean Symptom Severity after Baseline Adjusted Standard Error Non adherent Adherent Males Females Treatments AVR Alone AVR + Nurse assist with symptoms & adherence AVR Nurse adherence only AVR Weekly Calls

Least Square MEANS Symptom Severity during AVR 1-8 IVR calls *Green line: Symptom severity declined over the course of the intervention.

Trial Arm and Adherence Neither symptom severity or depression at intake was related to adherence Group by drug cycle interaction on adherence – Within Arms 2 and 3, patients in continuous drug cycle were more adherent – Within Arm 1, there was no difference in adherence between continuous and intermittent drug cycles

Automated Voice Response (AVR) System Monitors and reminds patients of dosing schedules Feedback to the patient and tailored advice on strategies Can identify and report adherence or persistent side effects to: – Nurses oncology navigators – Oncologists or practices Adds value for patients, payers, and practitioners Can evaluate care

Value of Monitoring for Patients Clinical decision-making Capacity to notify professional to contact patient when: – Not adhering (over or under) – Severe side effects are occurring Engages them in self care strategies for pattern of symptom response over time

AVR Patient Monitoring to Support Adherence Flexible, integrated approach Electronic patient-reported outcome Supporting individualized information gathering and distribution Patient monitoring and communications Integrated phone and web communications Outbound contacts/assessments Alerts (user-defined triggers) to providers Assessment protocol

Conclusion Symptom severity declined over time 33% of patients had adherence problems – However, at 8-weeks, adherence was similar in all arms Complexity of medication regimen influenced adherence Missed doses increased with medication complexity Main reasons for non-adherence: – Forgot to take medication – Overtook medication The more monitoring, the more problems surfaced The AVR was effective at symptom management and monitoring adherence

Future Research Future work needs to be done to identify reliable measures of oral agent adherence. Interventions need to focus on: – Clinicians eliciting patient frequent feedback on adherence – Simplifying the regimen (days on and off) – Identify medication reminders/technology – Developing supportive symptom management techniques – Patient education on value of efficacy of cancer treatment and relationship to adherence