Chemotherapy-Induced Nausea and Vomiting: Roles of Pharmacists and Formulary Decision Makers

Stacey W. McCullough, PharmD

Chemotherapy-induced nausea and vomiting (CINV) is among the most common and distressing adverse events (AEs) associated with chemotherapy.1,2 Despite advances in chemotherapy and the provision of expert guidelines in managing CINV, 80% of patients undergoing chemotherapy continue to experience CINV.3-5 The effect of CINV on patients is physically, mentally, and financially burdensome, resulting in increased direct and indirect costs and decreased health-related quality of life (HRQOL).6-11 While nausea and vomiting, and the resulting effects, are the main influencers of HRQOL, drivers of the financial burden of CINV include direct costs resulting from inadequate prophylaxis, indirect costs from diminished HRQOL, and the cost of noncompliance with cancer therapy such as disease progression due to CINV.

Understanding CINV
CINV can be categorized as acute, delayed, anticipatory, breakthrough, or refractory. 12,13 The initial incidence of CINV is predictive for CINV in subsequent cycles, and a lack of control of CINV in the acute phase is often predictive of an inability to control delayed CINV.14 However, delayed CINV can occur in patients who do not experience acute CINV.14 Factors affecting CINV include a history of nausea and vomiting (eg, motion sickness), age, sex, alcohol consumption, type and dosage of chemotherapeutic agent, administration route, and/or schedule.13 Studies have shown delayed CINV is more common than acute CINV and tends to occur in patients receiving carboplatin, cisplatin, cyclophosphamide, or doxorubicin.6,13,15,16

Chemotherapeutic agents have been classified according to the associated risk of inducing acute nausea and vomiting as high–emetic risk chemotherapeutic (HEC) agents, moderate–emetic risk chemotherapeutic (MEC) agents, and low–emetic risk (LER) chemotherapeutic agents. HEC agents, including cisplatin, dacarbazine, and high-dose cyclophosphamide (≥1500 mg/m2), cause CINV in >90% of patients.13,17 MEC agents, including carboplatin, cyclophosphamide <1500 mg/m2, anthracyclines, and oxaliplatin, cause CINV in 30% to 90% of patients.13,17,18 LER agents, including etoposide, methotrexate, taxanes, gemcitabine, pemetrexed, lenalidomide, and temsirolimus, are associated with CINV in 10% to 30% of patients. Fewer than 10% of patients experience CINV after receiving minimal emetic risk agents, including bleomycin, bevacizumab, vincristine, epidermal growth factor receptor inhibitors, and fludarabine.13,18

In a study evaluating 240 chemotherapy-naïve patients receiving MEC between April 2012 and May 2013, physicians estimated prophylaxis would be effective for 75% .16 However, despite receiving prophylactic treatment, 31% of patients did not achieve a complete response and 38% complete protection. Although nausea was better controlled than vomiting, late-phase response was not as well controlled as acute-phase response. In general, it was concluded that healthcare professionals overestimated the effectiveness of antiemetic prophylaxis; 56% of patients in the study were not even administered antiemetic medication for delayed-onset CINV.16

According to the National Comprehensive Cancer Network (NCCN) guidelines, the goal of emesis control is to prevent nausea and/or vomiting throughout the entire period of risk, which lasts for at least 3 days for HEC and 2 days for MEC after the last dose of chemotherapy.13 Effective treatment of delayed-onset CINV continues to be a significant problem in patients who receive chemotherapy, despite treatment guidelines.16

Consequences of CINV
Inappropriate treatment of nausea has a significant impact on HRQOL and may be a prognostic factor for overall survival.6,19-21 CINV can increase the risk of electrolyte imbalance, dehydration, epigastric pain, and other gastrointestinal complications. These can lead to rehospitalization, the need for hydration therapy, and reduced HRQOL, resulting in reduced participation in activities of daily living as well as health-related costs. 6,7 Uncontrolled CINV is also associated with noncompliance with anticancer therapy, which may further affect patient outcomes.1,10

Quality-of-Life Considerations
CINV can result in metabolic imbalances, degeneration of self-care and functional ability, nutrient depletion, and anorexia.13 The Functional Living Index-Emesis (FLIE) is a validated 7-point visual analog scale tool that includes 9 questions related to the effects of nausea and vomiting on activities of daily living as well as social and emotional functioning for up to 5 days after chemotherapy.22,23 It is one of many validated nausea- and vomiting-specific assessment tools used to measure the impact of CINV on HRQOL and daily living based on patient-reported outcome measures.

The Anti-Nausea Chemotherapy Registry (ANCHOR) study assessed the impact of acute and delayed nausea and vomiting after HEC and MEC on patients’ quality of life (QOL) using FLIE.6 Of the 298 patients in the study (67 patients on HEC, 231 patients on MEC), 59.7% reported experiencing nausea (36.2% acute, 54.3% delayed) and 36.4% reported vomiting (13.2% acute, 32.5% delayed). As expected, patients on HEC reported significantly lower mean FLIE total scores than patients on MEC (95.5 vs 107.8, respectively; P = .0049). Although 173 patients did not report either nausea or vomiting during the first 24 hours after chemotherapy, 22.9% reported an impact on daily life caused by delayed CINV.6 The ANCHOR study demonstrated that CINV adversely affects patient QOL, even after treatment with MEC regimens and in those who do not experience nausea and vomiting during the first 24 hours after chemotherapy.6

In another study of 178 patients undergoing chemotherapy, 61.2% reported experiencing CINV: 34.3% had acute CINV and 58.4% had delayed CINV.7 On average, patients reported CINV 1.76 days following chemotherapy. Reduced daily functioning due to CINV was reported in 37.2% of all patients, and of those with poorly managed CINV, about 90% reported FLIE scores indicating a significant impact on daily functioning.7 Conversely, of the patients with well-managed CINV who did not experience vomiting or did not need rescue medication (complete responders), 90% had an average FLIE score indicating no impact on daily living (NIDL). Only 36% of noncomplete responders had FLIE scores indicating NIDL.7 As such, QOL monitoring is important as part of comprehensive patient management that can result in improved changes in antiemesis treatment and potentially improved QOL outcomes.

Studies have demonstrated that QOL scales may be independent prognostic factors of overall survival in patients with cancer.19-21 One reanalysis of the impact of QOL in patients with hepatocellular carcinoma (HCC) found that better role functioning (HR, 0.991; 95% CI, 0.987-0.995) was associated with longer survival.20 This association was confirmed in another study of 489 patients with HCC using the Spitzer QOL index.19 A meta-analysis of 30 randomized controlled trials with survival data for 10,108 patients with 11 cancer sites found that HRQOL parameters of physical functioning (HR, 0.94; 95% CI, 0.92-0.96; P <.0001), pain (HR, 1.04; 95% CI, 1.02-1.06; P <.0001), and appetite loss (HR, 1.05; 95% CI, 1.03-1.06; P <.0001) provided significant prognostic information and could help predict survival in patients with cancer.21

Healthcare Usage
Dehydration, anorexia, and electrolyte imbalance often accompany CINV and can lead to rehospitalization, the need for hydration therapy, and reduced treatment compliance.15,19,24 In a retrospective, claims-based study of 1059 patients with solid tumors receiving therapy with anthracycline plus cyclophosphamide, cisplatin, or carboplatin, incidences of total CINV events and CINV-related emergency department (ED) visits were lower in the group receiving an NK1 receptor antagonist (44% and 9%, respectively) than in the group not receiving an NK1 receptor antagonist (50% and 15%, respectively).10 Patients in the NK1 receptor antagonist group also had a lower number of CINV-related office visits (40% vs 44%, respectively) and lower proportions of overall ED visits and hospitalizations. For patients receiving HEC or MEC, the treatment inclusion of an NK1 receptor antagonist, according to current NCCN guidelines for CINV, may reduce healthcare resource usage, including CINV-related office, hospital, and ED visits.10

Cost Considerations for CINV
The study of 178 patients with cancer previously mentioned found that those who reported severe nausea had higher average costs due to healthcare usage ($802.40 per patient) than patients who reported moderate ($32.30) or mild nausea ($6.70).7 Average total direct medical costs for patients receiving HEC were $819.16, compared with $674.05 for patients receiving MEC (P = .11). Total average direct medical costs for patients were $732.14, based on treatments prescribed and physician-reported healthcare usage. On average, the total cost for CINV was $778.58 per patient from the day of administration through the 5 days following the first cycle of chemotherapy, with higher costs for patients with more severe CINV.7

Another cost evaluation study showed that CINV affected up to 24% of patients on HEC and up to 32% on MEC, with nearly double the overall healthcare costs for patients with CINV.9 A retrospective cohort analysis assessed the cost of CINV in 5912 adult patients diagnosed with breast, lung, or colon cancer who were newly treated with single-day HEC or MEC and received a short- or long-acting prophylactic 5-HT3 receptor antagonist.9 The mean total healthcare cost in the first cycle for patients with CINV was $18,836 compared with $9582 for patients without CINV (P <.001).9 Similar results were seen in another retrospective analysis of medical claims of 2018 individuals with cancer treated with HEC or MEC.11 This study found that despite the use of a 5-HT3 receptor antagonist, 28% of patients had uncontrolled CINV, with an estimated increase of $1300 in monthly medical costs associated with uncontrolled CINV. The indirect costs per patient per month were $433 higher for those in the uncontrolled CINV group.11 Data have also shown that CINV-related hospitalizations and office visits were common in the first month after chemotherapy in patients treated with HEC or MEC.8

Indirect Costs of CINV
A cross-sectional survey using a dual sampling frame of 5532 patients with cancer found that 48% experienced treatment-related nausea/vomiting and that patients spent 4.5 hours, on average, per visit to treat AEs.25 Approximately 43% of the patients were employed, and of these, 78% were actively working. Of the employed patients, 46% reported working due to financial need, and 29% said, given a reduction in time spent at the doctor’s office, they would spend the surplus time working for pay.25 Across all demographic subgroups, the employed patients missed an average of 18 workdays annually due to treatment-related AEs (TRAEs). Doctor visits due to TRAEs forced 28% of patients to work part time when they wanted to work full time. Supportive care strategies that may effectively reduce AEs such as CINV may help improve patient productivity at work and reduce the overall time burden for treatment.25

Cost of Compliance
The most important impact of CINV could be its potential to lead to noncompliance with treatment, resulting in delays in chemotherapy administration, dose reduction, or interruption of therapy, thereby potentially impacting treatment efficacy.5,26,27 A survey of more than 2000 clinicians determined that CINV was associated with delayed or discontinued chemotherapy in approximately 30% of patients.28 One retrospective claims analysis of adults who initiated treatment consisting of single-day intravenous HEC or MEC regimens found that a treatment that more effectively reduced the occurrence of CINV in these patients also resulted in better adherence and fewer treatment delays than less efficacious antiemetic therapies.27

Improving Adherence
To ensure compliance with anticancer therapy, control costs, and improve patient QOL, it is imperative that healthcare professionals and managed care organizations (MCOs) intensify the detection of CINV and improve the management of these frequent, costly, and devastating AEs.26 Strategies to consider include healthcare professional and patient education, a review of benefit design to support patients, and formulary considerations that encourage long-term cost savings through prevention.

Gaps in CINV Management Among Healthcare Professionals
The results of a survey of healthcare professionals show that the majority are open to learning more about CINV and its treatment options. They express a strong interest in learning more about the prevention and management of breakthrough nausea and vomiting, emerging clinical data on CINV, and preventive treatment strategies.28 In this survey, 50% reported breakthrough nausea and vomiting as the most commonly encountered type of CINV and 33% reported delayed nausea as the most problematic to manage.28 Another survey reported that 95% of hematology/oncology physicians and 88% of nurses strongly agreed that CINV is well controlled in their patients, but as many as 32% of the hematology/oncology respondents reported that they delayed or discontinued chemotherapy in their patients during the past year because of nausea or vomiting.28

Healthcare professionals may not witness episodes of CINV. Therefore, it may be difficult to determine how poor the patient experience is, relative to professional expectations.29 It is imperative that healthcare professionals fully assess an individual’s risk of CINV and provide appropriate and timely guideline-based management of CINV. The treatment should be based on a comprehensive patient assessment, with proactive questioning about potential CINV risk factors before each chemotherapy cycle so that treatment is tailored to the individual patient’s needs and not solely reliant on emetogenicity of the chemotherapy regimen.29

Patient Education and Improving Adherence
Patient education is critical to treatment success, and the first step  is making certain that patients and providers are on the same page. However, experts emphasize that delayed CINV is underestimated and perceived differently by providers and patients.29,30

The results of a survey of providers recruited through the National Comprehensive Cancer Network and the Oncology Nursing Society (n = 141) and patients who received at least 2 cycles of chemotherapy and experienced CINV (n = 299) showed that the 2 groups differed significantly in their outlook on management of AEs and barriers to treatment.30 Providers frequently reported financial and patient-related factors as barriers to CINV management. Patients were less concerned about the cost of treatment and more about the number of medications they were taking than the healthcare professionals assumed; 37% of patients said they tried “to be strong by not complaining.”30

Communication is an important aspect of effective and quality care in the treatment of CINV, and addressing misconceptions and establishing mutually consistent goals may lead to more effective overall care.30 Encouraging patients to keep a diary of their symptoms can help healthcare professionals better understand the symptoms the patient is experiencing and the impact of the symptoms on the patient.29 Effective 2-way communication with accurate information may contribute to the development of a tailored CINV treatment regimen. Helping patients understand what to expect of their treatment, the type of symptoms to report, when to report symptoms, and ensuring access to a healthcare professional when needed are all part of an effective management strategy that is founded on open communication and patient education.

Ensuring effective treatment of CINV also requires that the patient have a clear understanding of the strategy behind prophylaxis versus symptomatic treatment.29 It is important that patients understand how to manage their symptoms and the role of their prescribed treatment in the management process. Emphasizing the need to comply with the doctor’s instructions and take their prescribed antiemetic medication as instructed, even in the absence of symptoms, is critical to ensuring adherence and preventing CINV.

Benefit Design to Support Patient Care
As previously discussed, improving adherence to anticancer treatment can improve clinical outcomes, reduce costs, and curtail TRAEs, such as CINV. However, another important aspect of treatment adherence is cost. Keep in mind that high out-of-pocket spending on cancer treatment is associated with decreased treatment adherence and poorer QOL.31 However, many employers are shifting the cost burden to employees with the logic that they will use healthcare resources more judiciously when they are held accountable for the costs.32 Recent data show that people with cancer who are younger than 65 years tend to continue working during their cancer treatment or return to work post treatment.33 Given advances in cancer care, many cancers may now be considered chronic diseases requiring long-term care or management, making it more likely for individuals to remain with the same employer for more than 5 years post diagnosis.33

With benefit trends shifting to place a greater cost burden on employees, employers and MCOs need to reanalyze how they manage the cost of medical care for their employees and prevent out-of-pocket healthcare expenditures from becoming cost-prohibitive. By looking at the clinical data over the long term, employers and benefit consultants will be able to design data-driven benefit plans that balance cost management with treatment efficacy and QOL management for their patients with cancer. Some important aspects of benefit design that may help include:

Ensure care that is driven by evidence-based guidelines and eliminate low-value prescribing practices13,32

Develop tools that assess patient financial health to ensure access to care32

Educate healthcare professionals on the need to assist patients in identifying payment assistance programs, such as manufacturer co-pay assistance or foundation assistance programs
Implement healthcare professional education programs that provide transparency to cost and allow them to help their patients make value judgments to determine their optimal regimen based on individual situation goals and circumstances34

A value judgment for CINV incorporates 4 factors: clinical, logistical, safety, and cost.34 Clinical factors include the benefit of controlled symptoms, which itself includes adherence to the chemotherapy treatment schedule, as well as QOL.34 Logistical factors are those aspects of the individual patient that the healthcare professional needs to take into consideration before developing a treatment regimen. These include the patient’s health literacy, the convenience or complexity of the regimen, and the likelihood of adherence to the treatment regimen. Based on the assessment of these factors, the healthcare professional can determine the level of education needed for the patient to comply with therapy and the need for communication between the healthcare professional and the patient.34 Safety factors include the AEs of the antiemetics themselves, and cost factors include affordability, coverage, and reimbursement.34

MCOs have improved some costs through the adoption of multitier formularies, prior authorization requirements, and automatic generic substitutions.35 However, a benefits design that supports patient care can help further curtail long-term costs for the healthcare system and society at large. By providing patients with the cancer care they need to complete their treatment cycles and minimize TRAEs, such as CINV, patients can optimally participate in the activities of daily living, including returning to the workforce.

Formulary Considerations
Effective formularies enable all healthcare professionals within a healthcare center, institution, or MCO to cohesively promote positive therapeutic outcomes and cost-effective medications. Drug formularies are intended to balance patient access and QOL with costs that can be sustained by the institution or organization. This is done through the use of evidence-based guidelines and the expert assessment of physicians, pharmacists, and other healthcare professionals.

The concept of formulary tiering of drugs had been criticized by some for limiting clinical autonomy and overly focusing on cost containment. However, others see tiering as guidelines to help direct physician thinking beyond marketing claims and toward the most appropriate and evidence-based choices, keeping costs in mind from a societal perspective.36 As part of the multidisciplinary care team, formulary decision-makers and managed care professionals have an opportunity to have a significant impact on patient care. Many of these healthcare professionals play key roles in:

Developing guidelines for treatment selection that are specific to the institution or the patient population they serve

Verifying inclusion of antiemetic treatments that can prevent or mitigate TRAEs

Ensuring implementation of appropriate guidelines for chemotherapy treatment selection

Helping to develop guidelines and formularies that incorporate patient-centered and value-based care can help prevent and mitigate AEs such as CINV and can result in outcomes achieved in a cost-effective manner using evidence-based care and data-supported best practices. When making decisions for adding to a formulary, it is important to consider the need of the agent, its safety and efficacy profile, its cost implications, and the quality of unbiased evidence supporting its use.36 The following is an overview of prominent issues to consider.36,37

Comparative efficacy
Potential for misuse
AE profile
Cost of treatment versus cost of delaying treatment or lack of treatment
Resource usage due to use of treatment versus delayed or denied treatment
Patient education on treatment use and adherence to achieve desired outcome
Monitoring treatment efficacy
Factors in favor of adding a treatment to an institution’s formulary include its ability to minimize potential risk, cost-effectiveness, and value to patient QOL.36,37

Conclusion
Despite treatment advances, CINV remains among the most common AEs associated with chemotherapy, impacting the physical and potentially mental well-being of 80% of patients undergoing chemotherapy. Effective treatment of CINV necessitates that healthcare practitioners and formulary decision makers understand the impact of CINV on patients, not only in terms of quality of life and physical symptoms, but also the indirect costs of CINV that result in loss of productivity. The burden of the disease should be weighed against the cost of preventing CINV; however, it is critical that the total financial burden of inadequate prophylaxis, due to diminished HRQOL, and the efficacy implications of noncompliance with cancer therapy due to CINV be considered as well. 
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