Abstract
Objective
Chemotherapy-induced nausea and vomiting (CINV) is a common and potentially debilitating adverse effect of chemotherapy. Refractory CINV can be particularly difficult to control. This report provides details on the implementation and evaluation of a pharmacist-led program for the management of refractory CINV in hematology and oncology clinics.
Methods
A pharmacist-led program open to adult outpatients with refractory CINV was implemented at University of Wisconsin. Pharmacists conducted baseline and follow-up assessments, provided patient education, and started, discontinued, and/or adjusted antiemetics as clinically necessary for all enrolled patients. Retrospective chart review was used to describe the proportion of patients whose CINV improved through pharmacist intervention, effect of the program on antiemetic adherence, categorization of pharmacist interventions, and duration of patient enrollment.
Results
Forty-six patients were enrolled between February 2019 and January 2020. Forty-one patients (89.1%) had an overall reduction in their nausea and vomiting from baseline. Eleven patients (23.9%) met criteria for nonadherence to prescribed antiemetics at baseline; all patients were adherent at unenrollment. A total of 111 pharmacist interventions were made. The most common intervention was addition of new breakthrough antiemetic. The least common intervention was dose escalation of a previously prescribed antiemetic. The average number of interventions made per patient was 2.5. On average, patients were enrolled in the program for 16.6 days and met with a pharmacist three times.
Conclusion
Implementation of this program standardized and streamlined pharmacist involvement with refractory CINV. Enrollment resulted in a measurable reduction in nausea and/or vomiting for patients with refractory CINV.
Introduction
Chemotherapy-induced nausea and vomiting (CINV) is a common and potentially debilitating adverse effect of chemotherapy for many cancer patients. The presence of CINV has been shown to negatively impact patients’ quality of life, ability to carry out daily activities, and willingness to continue chemotherapy. 1 CINV also has both indirect and direct financial implications stemming from additional utilization of healthcare resources and lost productivity from those affected. 1 CINV may manifest as acute nausea and/or vomiting, defined as occurring ≤ 24 hours after last chemotherapy treatment, or delayed, occurring > 24 hours after last treatment and typically lasting for at least two to three days. Prevention of nausea and vomiting is the goal of antiemetic use in CINV, and patients should be protected with antiemetics throughout the entire period of risk. 1 Patients may also experience anticipatory CINV, which occurs prior to a chemotherapy treatment in response to a negative experience with chemotherapy, and/or breakthrough CINV, which occurs despite prophylactic antiemetic treatment and may require rescue agents. Finally, refractory CINV occurs when antiemetic prophylaxis and rescue agents have not been effective for several cycles. 1 The categorization of chemotherapy agents as highly emetogenic chemotherapy (HEC), moderately emetogenic chemotherapy (MEC), or low- or minimal-emetic risk chemotherapy is considered in parallel with patient-specific factors such as age and sex when choosing the number and type of antiemetics used to minimize nausea and vomiting.1,2
Fortunately, the increasing number and effectiveness of antiemetics over the last twenty years has significantly decreased the incidence of chemotherapy-induced nausea and vomiting. 3 However, CINV control, particularly in the delayed phase, remains a problem for many patients. 4 Because delayed CINV is less visible to the healthcare team than acute CINV, underestimation of the incidence of this phase of CINV may contribute to poorer control. 5 Patient non-adherence to oral antiemetics may also lead to an increased incidence of nausea and vomiting. Patients who are not experiencing CINV in the days following chemotherapy may not understand the need for continued antiemetic prophylaxis, highlighting the importance of patient education. Conversely, patients who are experiencing CINV may be reluctant to take an oral medication for fear of worsening nausea and/or causing vomiting. 4 Finally, although adherence to guidelines has been shown to improve CINV control, guideline-consistent CINV prophylaxis for HEC or MEC has been reported to be as low as 57%.3,6
Refractory CINV presents a particularly difficult situation for clinicians. 2 This type of CINV has a considerable impact on patient quality of life and can be isolating, painful, and expensive. Patients with refractory CINV report feeling like a burden to loved ones, being scared or unable to leave home, and not wanting to continue with chemotherapy. Unfortunately, refractory CINV is not uncommon; 20% of patients who receive HEC or MEC experience it. 7 Although national guidelines provide recommendations on the treatment of refractory CINV, therapy choices are more complex and individualized; many factors, including patient risk, chemotherapy regimen, cancer type, previous therapies, and patient preference must be considered.
Pharmacist- and nurse-led CINV management programs have been successfully implemented in various forms at other institutions. In one retrospective study, pharmacist management of CINV for hospitalized adults was found to be as effective as provider management, as determined by number of breakthrough antiemetic doses required. Additionally, pharmacists in that program were found to be significantly more adherent to institutional CINV guidelines than providers. 8 In the clinic setting, a pilot of a pharmacist consult service for the management of CINV, as well as chemotherapy-induced peripheral neuropathy and women’s health, demonstrated that both physicians and patients found pharmacist management of these symptoms to be a valuable service. 9 A nurse-led program that implemented the completion of a risk factor assessment checklist and a follow-up phone call post-chemotherapy found that antiemetic adjustments were made in approximately half of patients enrolled in the program, proving that these programs are not only appreciated, but have substantial impacts on patient care. 10 More recently, a study evaluating a pharmacist-led CINV program that proactively enrolled patients on HEC regimens reported high rates of patients who achieved no CINV symptoms through pharmacist intervention. 11
It is imperative that antiemetic regimens be optimized quickly for patients with refractory CINV to prevent chemotherapy delays, dose decreases, or changes in agents, and to improve patient quality of life. Given their specialized training, consistent clinic presence, and access to provide direct patient care, ambulatory oncology pharmacists are in a unique position to improve patient outcomes, save provider time, and enhance clinic efficiency. This report provides details on the implementation and evaluation of a pharmacist-led program for the management of refractory CINV in hematology and oncology clinics within an academic medical center.
Methods
Program overview
University of Wisconsin Carbone Cancer Center (UWCCC) is a National Cancer Institute-designated comprehensive cancer center that services more than 5,000 patients from across Wisconsin and beyond annually. UWCCC employs 3.6 full-time equivalents of ambulatory oncology pharmacists who are embedded in multiple clinics, including gastrointestinal, genitourinary, gynecology-oncology, breast, hematology/bone marrow transplant (BMT), and lung cancers. These clinical pharmacists are intimately involved in the optimization of CINV prevention and treatment, among many other aspects of medication management including oral chemotherapy education, toxicity and adherence assessments, therapeutic drug monitoring, and supportive care medication education in the clinic setting.
Ambulatory oncology pharmacists at UWCCC may become aware of a patient with refractory CINV through several mechanisms, including pharmacist clinic visits, messages from a triage nurse, or messages, calls, or pages from nurses seeing patients in the chemotherapy infusion center. In this workflow, pharmacists who have identified that a patient is experiencing uncontrolled CINV first approach a provider to discuss therapy changes, reach a shared conclusion on appropriate antiemetic adjustments with that provider, and then prescribe for the patient using verbal orders. This multi-step workflow can slow the implementation of necessary treatment changes, particularly given variability in provider schedules. Patients receiving chemotherapy without a provider appointment may require antiemetic changes on a day their provider is not scheduled in clinic. Even when providers are in clinic, they may not be immediately available to discuss changes.
Management of CINV at UWCCC is directed by an institutional guideline. This guideline categorizes chemotherapy agents as high-, moderate-, low-, or minimal-risk and outlines preferred and alternative antiemetic regimens for each. Preferred prophylactic and breakthrough antiemetic regimens are incorporated into standard chemotherapy order sets in the electronic health record based on the emetogenicity of the chemotherapy regimen. Antiemetics can then be adjusted as needed on a patient-specific basis.
All patients with refractory chemotherapy-induced nausea and vomiting managed by an adult hematology/oncology physician were eligible for enrollment in the program, regardless of the categorized emetogenicity of the patient’s chemotherapy. The diagnosis of refractory chemotherapy-induced nausea and vomiting was made by the referring provider; patients did not need to meet specific criteria outlined by the program to be deemed refractory. Patients on active study for cancer treatment were excluded to avoid unintentional deviations from study protocol. Providers referred patients to the program via verbal or written communication to an ambulatory clinical oncology pharmacist, who would then manually add the patient to a report in the electronic health record (EHR) used to track all enrolled patients. This quality improvement study was exempt from Institutional Review Board (IRB) review.
Once enrolled in the program, a pharmacist conducted a baseline assessment either in-person or via telephone to gather information about incidence of nausea and/or vomiting per week, triggers for episodes of CINV, frequency of missed antiemetic doses, and reasons for any missed antiemetic doses. As part of this assessment, the patient’s nausea and vomiting was graded using the National Cancer Institute (NCI) Common Terminology of Criteria for Adverse Events (CTCAE) version 5. 12 The pharmacist then provided additional counseling on antiemetic adherence, optimized antiemetics, and assisted with other medication-related issues such as drug interaction assessment and adverse event education as needed.
An institutional protocol delegating authority from hematology/oncology physician to ambulatory oncology pharmacist to adjust antiemetics was created to enhance efficiency of this program (Figures 1 and 2). Through this protocol, pharmacists started, discontinued, or adjusted doses of antiemetics as clinically appropriate. The protocol specified that prophylactic antiemetic regimens could be escalated using institutional standard regimens as outlined in an institutional CINV guideline. For example, a patient with refractory CINV despite standard antiemetic prophylaxis for his/her low emetic risk chemotherapy could be escalated via protocol to receive the standard antiemetic prophylactic regimen for moderate emetic risk chemotherapies (Figure 1). Breakthrough antiemetics could be adjusted in a stepwise manner, with ondansetron optimized to maximum tolerated dose first, then prochlorperazine, then olanzapine. Pharmacists were also able to substitute granisetron for ondansetron in patients who were unable to tolerate ondansetron. If a patient required an antiemetic change that fell outside the scope of this protocol, the pharmacist would discuss the recommendation with the provider who would then prescribe the medication (Figure 2).
Example escalation of institutional prophylactic antiemetic regimens via pharmacist delegation protocol.a,b
Escalation of breakthrough antiemetics via pharmacist delegation protocol.a
Pharmacist follow-up was provided on weekdays approximately 72 hours after baseline assessment and each change in antiemetic therapy (Figure 3). At all follow-up encounters, further antiemetic changes or counseling were provided as needed based on evaluation of the patient’s CINV since the previous follow-up. This follow-up schedule continued until the patient was unenrolled from the program. Patient unenrollment occurred when one of four criteria were met: 1) at discretion of the provider, 2) current chemotherapy regimen was discontinued or completed, 3) nausea and vomiting resolved to NCI CTCAE grade 1 (nausea resulting in loss of appetite without alteration in eating habits and vomiting that does not require intervention), or 4) patient preference. 12 All CINV assessments, antiemetic changes, and pharmacist counseling points were documented in a progress note published in the patient’s EHR after every pharmacist appointment.
Pharmacist workflow.
Workflow implementation
Pharmacist workflows were presented at staff meetings and reviewed individually with all ambulatory oncology pharmacists. An overview of the program was also announced to physicians at meetings for all provider groups represented in the UWCCC. The program was initially piloted in the genitourinary, head and neck, and lung clinics. Feedback was solicited throughout the nine-week pilot and workflows were updated as necessary. After the pilot phase, the program was expanded to all oncology clinics at UWCCC simultaneously, including hematology/BMT, gastrointestinal, gynecology-oncology, and breast clinics.
Evaluation of CINV program
Retrospective chart review was performed for all patients enrolled in the program from February 20th, 2019 to January 14th, 2020. The resulting data was then summarized using descriptive statistics. Each patient’s nausea and vomiting was graded using NCI CTCAE at initial pharmacist assessment and all follow-up encounters. 12 Nausea and vomiting grades at baseline were then compared to grades at unenrollment to assess the proportion of patients whose CINV was improved through pharmacist intervention. Patients who reported grade 1 CINV at unenrollment were deemed to have a partial response, and patients who had no nausea and no vomiting at unenrollment were deemed to have a complete response. Additional outcomes assessed included antiemetic adherence, categorization of pharmacist interventions, and duration of program enrollment. Two measures of antiemetic adherence were documented at each patient appointment: 1) whether patients were taking scheduled and breakthrough antiemetics as prescribed, and 2) the number of missed antiemetic doses in a specific period. Patients were then categorized as either adherent (taking antiemetics as prescribed and no missed doses) or non-adherent (not taking antiemetics as prescribed and/or at least one missed dose). Breakthrough antiemetic doses that were intentionally omitted when symptoms were controlled were not considered missed doses. Impact of the program on patient adherence to prescribed antiemetic regimen was assessed by comparing patient reported adherence rates at baseline and unenrollment. Pharmacist interventions were placed into one of nine categories: medication counseling, adherence counseling, escalation of emetogenicity level/prophylactic antiemetic regimen, dose escalation of previously prescribed antiemetic, addition of prophylactic medication, addition of breakthrough antiemetic, scheduling of breakthrough antiemetic, extended dexamethasone duration, or other. The duration of program enrollment and number of encounters until unenrollment were collected.
Results
Program implementation
The CINV program pilot was implemented in February 2019 and expanded in April 2019. All pharmacists with hematology/oncology clinic responsibilities (n = 11) were trained on the program workflows. Providers were educated on the program prior to implementation.
Patient population
Forty-six patients were enrolled between February 2019 and January 2020. The median age of enrolled patients was 60 years, and 70% of patients were female. The most common diagnosis of enrolled patients was lung cancer. Fifty-four percent of patients were prescribed highly emetogenic chemotherapy regimens. Additional baseline characteristics are listed in Table 1.
Patient characteristics at study entry.
Includes non-small cell lung cancer and small cell lung cancer.
Includes squamous cell carcinomas of the floor of mouth and tonsil.
Patient outcomes
At baseline, the most frequently assigned CINV grades were grade 2 nausea and no vomiting. The most frequent CINV grades at unenrollment decreased to grade 1 nausea and no vomiting (Table 2). Forty-one patients (89.1%) had an overall reduction in their nausea and vomiting from baseline. A total of 29 patients (63%) had a partial response of their nausea and vomiting, while 12 patients (26.1%) had a complete response. The five patients who did not meet criteria for partial or complete response were unenrolled from the program prior to antiemetic optimization for two reasons: 1) patient preference (two patients), or 2) failure to meet definition of refractory CINV (three patients). No unenrolled patients required subsequent re-enrollment into the program. Eleven patients (23.9%) met criteria for nonadherence to prescribed antiemetics at baseline; all patients were adherent at unenrollment from the program.
CINV grades at baseline and unenrollment.
Pharmacist interventions
A total of 111 pharmacist interventions were made (Table 3). The most common intervention was addition of new breakthrough antiemetic, followed by medication counseling. The least common intervention was dose escalation of a previously prescribed antiemetic. The average number of interventions made per patient was 2.5, with a range of one to six interventions. On average, patients were enrolled in the program for 16.6 days and met with a pharmacist three times. Eight patients required greater than three pharmacist encounters, suggesting that their CINV was refractory to several antiemetic changes.
Pharmacist intervention categorization.
Includes lifestyle changes, medication calendar, addition of bowel regimen, addition of acid reflux medications.
Discussion
Chemotherapy-induced nausea and vomiting can be detrimental to patient quality of life and willingness to continue chemotherapy. Patients with refractory CINV, in particular, require additional time for assessment, antiemetic optimization, and close follow-up. A pharmacist-led program for management of patients who suffer from refractory CINV may lead to more efficient antiemetic changes and consistent follow-up. This report summarizes implementation of such a program at UWCCC.
Enrollment in this program resulted in decreased severity of nausea and vomiting for patients with refractory CINV. Most patients had grade 2 nausea at enrollment, meaning that oral intake was decreased without significant weight loss, dehydration, or malnutrition. 12 This niche group of patients who do not require in-clinic interventions such as intravenous fluids but do have persistent, refractory nausea seem to particularly benefit from pharmacist follow-up. Early interventions to address CINV for these patients may prevent symptom escalation that could impact treatment outcomes and be costly for both the patient and health system. Our program was designed as a consult service with a required provider referral. This design allows for targeted interventions to be made on patients who self-identify as struggling to manage nausea and/or vomiting, although it places responsibility on the patient to report symptoms. Proactive enrollment, or automatic enrollment with an opt-out option for providers, would increase capture of patients with refractory CINV. However, this type of enrollment is challenging for two reasons. First, diagnosis of refractory CINV was made by the provider using subjective patient criteria that is not easily tracked in the EHR and therefore cannot trigger automatic enrollment electronically. Additionally, because such a program would almost certainly enroll more patients, this method would be more likely to overwhelm pharmacist resources. Indeed, other programs that aimed for proactive enrollment of patients on HEC regimens have been unable to sustain all aspects of the program. 11 A hybrid model of consult service for some patient populations and proactive enrollment for others based on patient risk factors and the chemotherapy regimen used may be a feasible compromise. Our study found that patients on HEC regimens required more pharmacist encounters and a greater number of pharmacist interventions prior to unenrollment compared with patients on lower-risk regimens. Platinum-based chemotherapy comprised most (64%) of the prescribed HEC regimens. The most frequently enrolled patients by tumor type included those with lung cancer or head and neck cancer, and these patients were also among those with the longest enrollment times. This data suggests that these patient populations have more refractory CINV and may benefit from proactive enrollment in a pharmacist-led program. Consideration of pharmacogenomics, such as the implication of CYP2D6 phenotype on ondansetron metabolism, may also be factored in as this area of practice expands. 13 Other patients with refractory CINV could then additionally be referred to such a program through a consult mechanism. Our center has already seen provider engagement with proactive enrollment of patients at high risk for refractory CINV. Three high risk patients were preemptively enrolled in our program at the request of providers prior to the start of chemotherapy. Each patient was unenrolled when he/she ultimately did not meet the criteria for refractory CINV.
The most common pharmacist intervention in our program was addition of prophylactic antiemetic. Most enrolled patients received a three-drug prophylactic regimen at baseline, leaving room for a fourth anti-emetic, such as olanzapine, to be added. National CINV guidelines outline several appropriate options for prophylactic and breakthrough antiemetic regimens, resulting in anti-emetic standards that vary from institution to institution. 2 Interventions made through a similar program at another institution may therefore differ from our results. This program’s least common intervention was dose escalation of a previously prescribed antiemetic. Given that most enrolled patients were on a HEC regimen, many patients were receiving maximum dose of their prescribed anti-emetics at enrollment.
Additional counseling, both on anti-emetics and adherence, were also common interventions. Ambulatory oncology pharmacists at UWCCC provide supportive care counseling that includes antiemetic education at initiation of new chemotherapy regimens for all patients. Patients are again counseled on individual antiemetics at point of sale in the retail setting. However, since 23.9% of patients reported nonadherence to antiemetics at enrollment in this study, there appears to be additional benefit to continued counseling on antiemetics. Reasons for non-adherence may vary, and pharmacist education must be tailored to individual patient understanding. Methods such as visual guides explaining antiemetic directions or use of the teach-back method should be employed when needed. 14 Additional consideration of risk factors for nonadherence, such as low health literacy or history of nonadherence, may help identify those patients who may particularly benefit from enrollment in such a program.
Criteria for unenrollment from pharmacist-led programs varies in the literature. Hughes et al evaluated percent of patients with no nausea or vomiting at pre-specified times in the chemotherapy cycle. 11 Conversely, patients who were unenrolled from our program may still have had some nausea and/or vomiting, as criteria for unenrollment required only that CINV had decreased to at least a grade 1. The lack of re-enrollment of previously unenrolled patients in our program suggests that the education pharmacists provided to these patients allowed them to adequately manage their grade 1 CINV. Unenrolling patients with this criteria may help to appropriately direct pharmacist resources.
Future directions
Based on these positive results, expansion of this pharmacist-led CINV management program is being explored at UWCCC in several ways. In addition to the service for refractory patients, we hypothesize that particular groups will benefit from proactive enrollment at initiation of chemotherapy regimen. These populations include bone marrow transplant patients and patients scheduled to receive HEC regimens. Growth of the delegation protocol to include more antiemetic prescribing authority for pharmacists may be considered. Additionally, our organization is planning on evaluating value-added components of pharmacist management from the perspectives of providers, nurses, and pharmacists who interface with the program via an electronic satisfaction survey.
Limitations
Limitations of this quality improvement study include that pharmacist assessment of patient adherence was quantified only as a binary response (“adherent” or “non-adherent”). Additional information on reason(s) for nonadherence and counseling provided would be useful to both identify patients at risk for nonadherence and provide effective counseling for this patient population in the future. Additionally, diagnosis of refractory CINV was made based on subjective criteria at the discretion of the provider. The threshold for what was considered refractory therefore may have differed from provider to provider. Our sample size was also limited to 46 patients at a single institution. Lastly, cycle number at enrollment to the program was not collected. Since enrolled patients were deemed to have refractory CINV, all patients had received at least one previous cycle of chemotherapy. However, data on antiemetic changes made in previous cycles and length of time from diagnosis of refractory CINV to enrollment is unknown.
Conclusion
Implementation of this pharmacist-led CINV management program standardized and streamlined pharmacist involvement with refractory CINV. Patient enrollment in the program resulted in a measurable reduction in nausea and/or vomiting for patients with refractory CINV. The implemented consult model allowed for sustained pharmacist participation, while also identifying patients at high risk for refractory CINV who may benefit from proactive enrollment in a pharmacist-led program in the future.
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.
