Abstract
Introduction
Patients on oral oncolytics are responsible for self-monitoring adherence and adverse drug reactions (ADRs). Oncology pharmacists are in position to focus on quality and safety of care for patients on oncolytics while providing communication between the patient, physician, and specialty pharmacies. This pilot aimed to monitor patients treated by our leukemia team initiated on oral oncolytics.
Methods
From July 2020 to February 2021, patients treated by our leukemia team newly started on oncolytics were included. Pharmacists performed medication reconciliation and drug interaction screening on initiation of oral oncolytic. Pharmacists followed up at predefined intervals. On follow up adherence was assessed using the Morisky Medication Adherence Scale-8 (MMAS-8) and patient reported outcomes (PROs) were assessed using the revised Edmonton Symptom Assessment Scale (ESAS-r). After each follow-up, a note was placed in the chart with assessment scores and recommendations.
Results
A total of 32 patients were screened with 19 patients included. Oral oncolytics included: imatinib (4), dasatinib (5), ponatinib (1), gilteritinib (2), enasidenib (1), and venetoclax (6). Fourteen drug interactions were identified, 11 medications discontinued, nine medications added, and two medications doses were changed. Twenty-six adherence assessments were performed with 21, 4, and 1 assessment demonstrating adherence, medium adherence, and low adherence, respectively. 62 ESAS-r assessments were performed with 64% reported as no symptoms, 17% as mild, 13% as moderate, and 5% as severe symptoms. Twenty laboratory tests were ordered from pharmacist recommendation on initiation and follow-up.
Conclusion
This pilot demonstrated the role pharmacists play in oral oncolytic monitoring and symptom management.
Introduction
Oral oncolytics are a growing treatment option for oncology patients, increasing from 5% of chemotherapy agents in 2003 to 25–35% of agents in development by 2010.1,2 Although oral oncolotyics are an attractive treatment option for many patients due to the ease of administration and reduced time away from home or work, the burden of adherence and adverse drug reaction (ADR) self-monitoring largely depends on the patient compared to intravenous (IV) chemotherapy. 3
Reports of barriers to proper self-administration of oral oncolytics include forgetting to take doses, wanting to prevent ADRs, not understanding or reading administration directions, and not understand drug–drug or drug–food interactions.4,5 Poor patient adherence to oral oncolytics can have severe consequences and has been correlated to poorer patient outcomes in previous studies. Notably, the ADAGIO trial of patients with chronic myeloid leukemia (CML) on imatinib found a suboptimal response was significantly correlated to a higher mean percentage of imatinib doses not taken as compared to those with an optimal response (23.3% of doses not taken compared to 7.3%, p = 0.005). 6 Currently, there is no standard for measuring adherence to oral oncolytics and the literature of adherence rates varies greatly based on the different methods used. 5 The Morisky Medication Adherence Scale-8 (MMAS-8) is an adherence tool that has been validated in a variety of chronic diseases such as hypertension, psychiatric diseases, and asthma.7,8 It is a quick, self-reported survey consisting of eight questions, which assess medication adherence based on either forgetful or intentional behaviors. 8
Patient-reported outcomes (PROs) are an important way to monitor ADRs and assess contributing factors to medication non-adherence. Even in a tightly controlled clinical trial environment, physician reporting is not always sensitive or specific in identifying common chemotherapy ADRs. 9 PRO use has been associated with improved quality of life, fewer emergency room (ER) visits, and longer time on treatment regimens. 10 There are a variety of PRO assessment tools, including the modified Edmonton symptoms assessment system (ESAS-r) and the patient-reported outcomes common terminology criteria for adverse effects (PRO-CTCAE). ESAS uses a scale of 1–10 to assess key symptoms such as pain, fatigue, sleepiness, nausea, appetite, shortness of breath, depression, anxiety, and general well-being. Variations have been validated in the outpatient oncology settings.11,12 The CTCAE is the standard for reporting ADRs in oncology clinical trials and uses a grading scale of 1–5 for specific ADRs. 13 These two tools when combined can give a general symptom and drug-specific adverse effect assessment.
Guidelines exist for the best practices for the management of oral oncolytics; however, these guidelines only provide a framework recommending points of education and utilizing adherence/PRO assessments. 14 Specialty pharmacies assess for adherence and ADRs; however, there is no standard adherence or PRO assessment recommended in current guidelines. Physicians may not communicate directly with specialty pharmacies when issues arise. Oncology pharmacists are in a unique position to focus on the quality and safety of care for patients with cancer on oral oncolytics while providing communication between the patient, physician, and specialty pharmacies. In an effort to increase communication and improve safety, we propose a pharmacist-led oral oncolytic monitoring program in patients treated by our leukemia team. This program included patient education when oral oncolytics is initiated, as well as follow-up at standardized time points throughout their course of therapy for adherence and PRO assessments. Pharmacists assessed for drug interactions if new medications were added, as well as making sure all laboratory parameters required for specific oral oncolytics have been monitored. The goal of this program is to assess adherence and PROs during periods of time that patients may not be seeing a physician.
Methods
Prior to this pilot, an oral oncolytic drug review was created with physician approval that included standardized monitoring for each oral oncolytic used for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPNs), and myelodysplastic syndrome (MDS). Minimum laboratory assessments were defined for each oral oncolytic based off prescribing information recommendations, analysis of ADRs from previous studies, and clinical judgement. In addition to pre-specified laboratory monitoring, two progress note templates were created for each agent for initiation of oral oncolytic and follow-up. These notes included the pre-specified monitoring recommendations agreed upon above.
From July 2020 to February 2021, patients with leukemia, MDS, or MPNs newly started on oral oncoyltics were included in this monitoring pilot. Patients were identified by physician referral or pharmacist identification from oral oncolytic dispense reporting. Patients were excluded if they were non-English speaking as a majority of follow-up was done via phone calls. Patients were also excluded if they were on an oral oncolytic for less than two weeks, or if patients were unable to be reached upon follow-up. Upon initiation of oral oncolytics, the oncology pharmacist conducted a medication history and reconciliation, drug interaction analysis, and ensured required baseline labs were ordered. Pharmacists then scheduled an initial oral oncolytic education with the patient either by phone or during their next clinic appointment. After the initial teach, the pharmacist placed a progress note from the oral oncolytic initiation progress note template. Physicians were contacted via email that the education was complete. If there were clinically significant findings, physicians were paged to discuss further.
After initiation of oral oncolytic, a pharmacist followed up with patients every two weeks for the first two months, and then monthly thereafter up to six months from initiation of oral oncolytics. After six months of stable dosing, the pharmacist decreased the frequency of calls to every three months. On follow-up, pharmacists reviewed labs and recommended any missing monitoring parameters from the previously agreed upon monitoring plan. Either via phone call or clinic visit, the pharmacist performed a medication history and reconciliation with the patient at follow-up. Key education points were reviewed with the patient. After researching adherence and PRO assessments, the MMAS-8 and modified ESAS-r were chosen to assess adherence and PROs at each follow-up, respectively. The MMAS-8 was chosen for its high validity and reliability in chronic disease states, as well as the ease of administration with yes or no questions. The modified ESAS-r was chosen due to current literature supporting its use with oral oncolytic as well as encompassing key ADRs seen with oral oncolytics.
If patients had 2–3 adherence assessments demonstrating high adherence, no further assessment occurred on subsequent follow up encounters. CTCAE was utilized for ADRs specific to each oral oncolytic that were not covered in the modified ESAS-r. If patients identified an ADR, pharmacists recommended supportive care strategies. After each follow-up, the pharmacist emailed the physician any pertinent findings or recommendations and placed a note in the chart with the previously created follow-up template.
Data for the project were collected in real time during phone interactions with patients and immediately after in person interactions. Retrospective chart review of the electronic medical record was also performed to collect laboratory data, review medication history and active medications, and to assess for emergency department visits and hospitalizations. Descriptive statistics were utilized to document the specific activities pharmacists performed during this project and the number of interactions pharmacists had with patients to report the impact pharmacists had during this project. Descriptive statistics were also used to report common ADRs and outcomes patients’ experience, and to document the disease states and oral oncolytics encountered. Institutional review board (IRB) approval was not obtained for this project as this was deemed to be a quality improvement project. The aim of this pilot was to identify types of activities that could be added regarding oral oncolytic management outside of our current practice model while utilizing standardized assessments.
Results
A total of 32 patients were screened and 19 patients were included. Reasons for exclusion included non-English speaking (n = 2), patient refusal (n = 5), altered mental status (1), on oral oncolytic less than two weeks (n = 2), and not able to reach for follow-up (n = 3). The median age was 66 years with the majority of patients’ underlying malignancy being AML (37%) and CML (37%). Baseline demographics can be found in Table 1. The Charlson Comorbidity Index was used to define comorbidities. 15
Baseline demographics.
Comorbidities defined by Charlson Comorbidity Index.
A pharmacist was involved in choosing a dose prior to the prescription being written in 7 (37%) cases and 10 baseline labs were added after pharmacist review prior to medication start. Of the 19 patients included in the program, all received oral oncolytic education from a pharmacist at the time of medication initiation, with 79% of the education occurring in the inpatient setting. The median time spent on initial oncolytic teach was 15 min (interquartile range [IQR] 10–18), and the median overall time spent working on each new patient was 30 min (IQR 25–30). Pharmacist activities on oncolytic initiation can be found in Table 2.
Pharmacist activities for initial oral oncolytic teach.
The pharmacist completed a medication reconciliation at the time of initiation in 14 cases (74%) and completed a total of 53 medication reconciliations on follow-up encounters. Medication reconciliations were not performed at initiation if it was already completed by a different party upon initial admission to the hospital prior to starting the oncolytic. Reconciliations were not performed on follow-up encounters if the patient declined reviewing the medication list. At the time of initial medication reconciliation, 12 drug interactions with the new oral onclytics were identified; two drug interactions were identified on follow up encounters. Of the drug interactions identified, one would have resulted in decreased oral oncolytic serum concentration, five would have resulted in increased serum concentration, and six would have resulted in increased side effects of concomitant medications. Following the medication reconciliation, 11 medications were discontinued from patients’ medication lists, nine medications were added, and two medication doses were changed.
Twenty-six adherence assessments were performed which found 21 cases of adherence, four cases of medium adherence, and one case of low adherence. The median time spent with the patient during follow-up encounters was 10 min (IQR 10–15) and the overall median time spent working on each encounter was 25 min (IQR 20–29). Medication reconciliation and adherence data can be found in Table 3.
Medication reconciliation and adherence assessments.
*If two medications for the same patient would have resulted in the same effect, it was only counted as 1.
Pharmacists performed and completed a total of 62 follow-up encounters, 49 (79%) of which were performed in the outpatient setting. Based on chart review and clinical assessment at the time of the follow-up, pharmacists recommended a total of 10 labs for oral oncolytic monitoring on follow-up. Characterization of follow-up encounters can be found in Table 4. Pharmacists completed 62 patient-reported outcomes surveys and found 64% with no reported symptoms, 17% with mild symptoms, 13% with moderate symptoms, and 5% with severe symptoms. PRO assessment results can be found in Tables 5 and 6. Based on the assessment of PRO scores, pharmacists added supportive care in nine cases. The most common supportive care recommendations involved nausea and vomiting management and constipation management. In one case, a pharmacist recommended that a patient contact the cancer center as the patient reported being febrile and was at risk of neutropenia secondary to leukemia and the oral oncolytic they were receiving; the patient was subsequently admitted to the hospital for febrile neutropenia. Another notable intervention occurred when a patient reported their atovaquone monthly co-pay was $1500 and they expressed difficulty affording this. This was brought to the attention of the patient's oncologist and a recommendation was made to switch to trimethoprim–sulfamethoxazole, a more affordable alternative with a $20 copay. The oncologist accepted this recommendation and switched the patient's therapy, thus significantly decreasing the patient's medication cost burden due to the pharmacist's intervention.
Pharmacist follow-up.
Patient-reported outcomes-ESAS.
Patient-reported outcomes-CTCAE.
Discussion
This pharmacist-led oral oncolytic monitoring pilot demonstrated types of additional activities clinic oncology pharmacists may perform in an attempt to increase adherence and identify ADRs. We previously described a pharmacy resident-led medication reconciliation and patient education service in patients with leukemia receiving oral oncolytics. 16 From this previous pilot, we identified a need for patient education and longitudinal follow-up. We also learned of barriers in the implementation process, which were streamlined in this next pilot. These barriers included identifying patients, patients not understanding what a specialty pharmacy is, and strategizing how to track patients.
Identifying patients was a barrier in our previous pilot, whereas in this pilot, we were able to run a weekly report of patients who had prescriptions written for select oral oncolytics. In addition, as providers became more familiar with the services offered, we found more patients being referred for education and medication reconciliation upon initiation of oral oncolytics. A second barrier previously encountered was limiting the patient education encounter to matters pertaining only to oral oncolytic education. Since this first pilot, our center's specialty pharmacy started servicing oral oncolytics for our leukemia team. With the help from specialty pharmacy staff, the oncology pharmacist on site was able to focus on education while specialty pharmacy staff worked on prior authorizations and delivery coordination. Time constraints continued to be a barrier as pharmacists were often staffing inpatient while performing initial education or completing follow-up phone calls.
Often the specialty pharmacy process can be confusing for patients. On initial education, our clinic pharmacists introduced to patients what a specialty pharmacy is, who would be contacting them, and how they can obtain refills. We were regularly in communication with our specialty pharmacy for any new prescriptions being sent or dose changes being made. Although the Utilization Review Accreditation Commission (URAC) has set standards for specialty pharmacies, these standards guide minimum frequency of contact with the patient, with no set standard for what tool to use in adherence or PRO monitoring. Our specialty pharmacy continued their standard education and adherence assessment, while our clinic pharmacists were running this pilot. For unknown reasons, we did notice many patients refusing initial oral oncolytic education from the specialty pharmacist, despite our specialty pharmacists working closely with our clinic pharmacists. Because our specialty pharmacy is geographically located in a different location, we speculate patients thought of our specialty pharmacy as a separate entity versus an extension of the care through our institution.
One barrier we did not find a solution for was strategizing how to track patients due for follow-up interventions. In this pilot, we used an encrypted institution database to maintain a spreadsheet with each patient, the oral oncolytic they were on, primary oncologist, oncolytic start date, next follow-up date, and notes from previous follow ups. After completion of a follow-up, pharmacists put an invitation in their calendar of when the patient’s next follow-up should be. This process took more time and had opportunities for error. In the future, it would be helpful to find a way to track these patients within our electronic medication record.
It is well-known adherence can lead to improved outcomes as evidenced in the ADAIGO trial with imatinib in CML. 6 Despite this, adherence to oral oncolytics continues to be problematic for a multitude of reasons. To better understand the patient perspective on barriers to adherence, a 30-question survey was administered to address frequency and rational for skipping doses of oral oncolytics. 93 patients completed this survey with barriers identified including never looking at the labeling (39%) and difficulty reading the label (15%). Only 70% reported they never forgot to take their oral oncolytics, while 77% responded they never intentionally cut back or reduced doses. Of the patients who cut back on their oral oncolytic (n = 21), 38% did not tell their physician. The main patient-perceived barriers included: timing of drug with food, stopping drug without informing their physician, and difficulty understanding the label. 3
Despite adherence issues reported in the literature as above, 21 out of 26 adherence assessments performed in our pilot demonstrated adherence. Only four patients reported medium adherence and one patient reported low adherence. Motivational interviewing was utilized to identify barriers with patients and problem solve methods for remembering to take medications. Either the patients in this pilot demonstrated excellent adherence, or the adherence assessment tool did not capture true adherence rates. The MMAS-8 adherence scale was chosen as an assessment model as it was short, easy to administer, and previously demonstrated validity in select chronic disease states. Drawbacks to this assessment are the yes/no questions do not leave room for open-ended responses that could be expanded on if signs of adherence issues.7,8 This is the first reporting of utilizing the MMAS-8 adherence assessment for oral oncolytic adherence assessments. Our recommendation for future oral oncolytic monitoring pilots is to explore other adherence assessments. Other adherence assessments that could be utilized in future oral oncolytic monitoring programs include a 30-question survey previously discussed, Beliefs about Medicines Questionnaire (BMQ), the Medication Adherence Rating Scale (MARS), and Wilson's Three-Item Self-report Measure.3,4,17–20
In addition to adherence assessment, there is not yet a standard PRO assessment recommended upon specialty pharmacies or for physicians specific to monitoring ADRs related to oral oncolytic. The importance of PRO assessments was demonstrated in phase II of patients with prostate cancer where physician's assessment of ADRs in a clinical trial was not as sensitive or specific as a quality-of-life questionnaire. 9 In eight practices in Michigan, the ESAS-r assessment tool was used to collect and analyze 1235 surveys to analyze for PROs. 21 This group demonstrated a PRO assessment that can be implemented for oral oncolytic. We found the ESAS-r assessment model to be easy to administer while capturing many key ADRss seen with oral oncolytic. To tailor the PRO assessment to specific oral oncolytics, we added ADRs specific to certain oncolytics to ensure we captured the most possible ADRs. For example, taste change was assessed with enasidenib while volume overload was assessed with imatinib and dasatinib. Although we found the ESAS-r assessment tool to be valuable in identifying ADRs, because we mostly administered this assessment over the phone by asking each question and having the patient give us a number, the survey sometimes took a significant amount of time depending on the patient. In the future, if we could identify an electronic way to administer this survey and route survey to pharmacists when completed, this would free pharmacists up to analyze the survey and work through supportive care options with the patient.
There has been a plethora of literature demonstrating the role of oncology pharmacists in the clinic setting.22–28 Our oral oncolytic monitoring program is not unique in idea, but does add to the literature demonstrating types of activities that can be performed outside of standard physician/specialty pharmacy practices, and the utility of two different standardized assessments. There is currently no literature using the MMAS-8 to assess adherence to oral oncolytics. Secondly, there is no literature specifically using these assessments for oncolytics specific to leukemia. Although the types of activities were not exactly novel, this pilot serves as an example of pharmacists with limited resources expanding their role to identify needs related to oral oncolytic monitoring. This pilot was carried out by two inpatient pharmacists following our patients on oral oncolytics who were outpatient. This pilot taught us how our workflow can be improved, benefits of using the ESAS-r PRO assessment tool, and the need to explore alternative assessment tools. Although we learned a lot during this pilot, we cannot feasibly continue this pilot with the current staffing model without burning out our current staff, which has been an issue arising to the forefront of oncology pharmacy.
Although not measured in this pilot, we would be remiss to not discuss the risk of burnout in oncology pharmacy with expanding services similar to ours and lack of addition of full-time employees. Despite the benefit of oncology pharmacists, oncology pharmacists are experiencing a high rate of burnout according to a recently published survey. Out of 614 oncology pharmacists, 62% reported burnout based on the Maslach Burnout inventory (MBI) and Well-being index. Pharmacists experiencing burnout worked significantly more hours per week compared to those without high burnout. Pharmacists experiencing burnout spent on average 7.5 h a week on administrative tasks versus 3.4 h in those not experiencing burnout (p < 0.001). 29 Although this pilot increased job satisfaction for our oncology pharmacists through increased direct patient care, the time required to support this program was not met with the current staffing model at the institution. At times, pharmacists were required to run from inpatient rounds to outpatient visits to capture patients or stay late calling patients after their shift had ended. The previously discussed survey demonstrates our institution is not the only institution where pharmacists may be trying to expand practice with limited resources. To continue to support pharmacists in increasing safety and efficacy of oral oncolytics, similar to our pilot here, support through cancer centers outside of the pharmacy departments needs to be provided.
Conclusion
Over an eight-month period, pharmacists identified drug interactions, gave dose recommendations, recommended laboratory monitoring, assessed patient adherence, and provided symptom assessment and supportive care recommendations for patients with leukemia, MDS, and MPN newly initiated on oral oncolytics. This pilot program demonstrated that pharmacists play a supportive role in oral oncolytic management and monitoring, as well as symptom assessment and management. Future directions include identifying an electronic database to track patients due for follow-up and identifying or creating a database that can administer PRO assessments electronically and send to pharmacists for review. Our team will continue to explore alternative adherence assessment tools to utilize to improve adherence for patients on oral oncolytics. Lastly, this pilot demonstrated the need for pharmacist support in clinic, as this pilot would not have been able to be carried out by an inpatient team without over-extending pharmacists and increasing risk of burnout.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
