Study Design and Cohort. This was a single arm, clinical pharmacist-led, pre-post feasibility intervention study. We targeted patients at high risk for nonadherence or early discontinuation of AET medications rather than all patients, given many will be adherent without intervention. Since observed nonadherence is one of the few strong predictors of future nonadherence, high risk status was based on having already demonstrated nonadherence [27]. Our potentially eligible study sample pool was created using the electronic health record (EHR) to identify patients receiving AET therapy from month 9 (to allow calculation of nonadherence) through month 42 (to allow time for the intervention before therapy would be complete at 60 months). Nonadherence was defined as obtaining <80% of all expected daily scheduled doses [28]. Nonadherence for any 6-month period in the prior 18 months was calculated based on a medication possession ratio from pharmacy refills in the Surescripts electronic all-payer, all-pharmacy claims database, and was confirmed by telephone with the patient’s pharmacy/ies. Other inclusion criteria included being seen by the practice’s oncology practitioner(s) in the prior 18 months, having no evidence of recurrence, and having internet access to complete surveys.
Potentially eligible patients were sent an informational letter by mail/email, followed by a telephone call to describe the study, confirm eligibility, and enroll after an informed consent process. The Medical College of Wisconsin Institutional Review Board approved this study.
Symptom monitoring. We used REDCap [29] to manage patient data, including the symptom monitoring assessments underpinning the intervention as well as the PROs (described later). Participants were sent automated reminders by email or text with a link to complete symptom monitoring assessments weekly for 1 month and then monthly until 6 months. Reminders were sent each day if the assessment was not completed. After 3 reminders (3 days), a study coordinator called the participant to remind her to complete the assessment. Symptoms were assessed using 14 items from the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™), a flexible system designed to capture basic information (e.g., frequency, severity) about treatment toxicities in oncology settings.[30] We randomized the order of the questions in each administration. The monitoring assessments took approximately 1.5 minutes to complete (median 1.3 minutes, range 1-5 minutes). As in previous studies, [31] the two most severe response options (e.g., a score of 3 or 4 on a 0-4 scale) or a worsening of 2 or more points triggered follow-up for management.
Symptom management. After patients completed their initial symptom report, a clinical pharmacist met with the patient to discuss results of the report, respond to questions/concerns, and make recommendations for management strategies. The pharmacist was tasked to use a summary of evidence-based interventions focused on the most common symptoms among AET users (musculoskeletal symptoms, menopausal symptoms, and fatigue) that was developed by the clinical members of the research team (JN, EW, MS, SK, CO, KF). Primary sources included three guidelines based on systematic literature reviews; [15-17] treatments supported by randomized trials published after guideline publication dates and details from trials referenced in guidelines were also used (Table 1 and Appendix Figure 1 for full guideline). Pharmacists’ licensing in Wisconsin and 45 other states do not allow direct prescribing, but pharmacists were encouraged to provide symptom-relieving recommendations to the oncology provider team (physicians and/or advanced practice providers) for signature. The symptom management intervention was accompanied by other recommended elements of pharmacist medication management visits; [32] these elements included medication reconciliation from all available sources, confirmation of patient agreement with list, medication interaction checks, [33] reminder tool advice, and advice to the oncology team about and reducing other medications’ dosing burden or cost. After each patient interaction, pharmacists recorded time spent with the patient and the content discussed within the EHR. Safety procedures were in place for symptoms suggesting an acute problem, including pathways for referral to mental health providers.
After the initial visit, a pharmacist followed up with patients to ensure that they were able to follow through on any initial management recommendations (e.g., has information about yoga studio, prescription picked up), and then again to follow-up on the impact of the recommendation on the patients symptoms. The timing and communication method of these follow-ups varied depending on patient needs. If required, additional recommendations were made to palliate symptoms.
For the duration of the 6-month study, any new severe symptoms reported by patients in response to prompted symptom monitoring were sent to the pharmacy team with a copy to the oncologist. Clinical pharmacists then conducted additional management phone calls with patients in the same way as described above.
Pharmacist training
To mimic current care practices and enhance future dissemination, decisions including whether the visit should be in-person or telephone, and the tailoring of the visit elements were based on patient preference and pharmacist judgment. However, to ensure similar practices across pharmacists, all members of the clinical pharmacy team received a sixty-minute training session (Table 1). The session focused on side effect amelioration using the guideline summary developed by the investigator team, other medication management elements, and teaching around interpretation of PRO results.
Intervention refinement
Outcome assessments
We collected comprehensive PRO assessments at baseline, 3, and 6 months that covered a broad set of physical, mental, and social health domains, as well as self-efficacy to manage symptoms and self-efficacy to manage medications (domains listed in Table 4). We used Patient-Reported Outcome Measurement Information System (PROMIS) computerized adaptive tests through REDCap for the outcome assessments. PROMIS is the NIH’s initiative to standardize measurement of PROs in clinical research across all chronic conditions [34]. PROMIS measures have a U.S. population mean of 50 with SD of 10, and differences/changes of >3 points is typically considered meaningful. We describe baseline PRO scores in comparison to US and SEER reference populations as well as changes in PRO scores over time. We also assessed end-of study adherence, calculating it as obtaining <80% of all expected daily scheduled doses [28] for the 6-month period. As for enrollment, adherence was calculated based on a medication possession ratio from pharmacy refills in the Surescripts electronic all-payer, all-pharmacy claims database, and was confirmed by telephone with the patient’s pharmacy/ies.