Outcomes Associated with 5-HT3-RA Therapy Selection in Patients with Chemotherapy-Induced Nausea and Vomiting: A Retrospective Claims Analysis

Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of chemotherapy, and may present during or soon after (0-24 hours) chemotherapy administration (ie, acute CINV) or between 25 to 120 hours after chemotherapy administration (ie, delayed CINV).^1,2 In the absence of antiemetic prophylaxis, many emetogenic agents will cause emesis in more than 90% of patients within 24 hours of the administration of chemotherapy.^1-3 Preventing CINV during the initiation of chemotherapy is important, because the risk for CINV in future chemotherapy cycles increases if CINV occurs in the first or previous treatment cycle.^4-8 The 5-hydroxytryptamine₃ receptor antagonists (5-HT₃-RAs) have proved to be very effective in the prevention of CINV, with current guidelines supporting the use of the 5-HT₃-RA agents for CINV prophylaxis.^9-11

Despite the effectiveness of the 5-HT₃-RAs, uncontrolled CINV still occurs in more than 25% of patients receiving chemotherapy.⁴ Antiemesis guidelines from the American Society of Clinical Oncology, National Comprehensive Cancer Network (NCCN), and Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology (MASCC/ESMO) recommend palonosetron as a preferred treatment among the 5-HT₃-RAs for CINV prophylaxis before moderately emetogenic chemotherapy (MEC).^9-11 In addition, the NCCN’s antiemesis guidelines have granted palonosetron preferred status for the prevention of CINV with strongly emetogenic chemotherapy (HEC) regimens.¹⁰ The MASCC/ESMO guidelines consider palonosetron as the preferred 5-HT₃-RA for anthracycline plus cyclophosphamide chemotherapy regimens when a neurokinin 1 receptor antagonist is not available.¹¹

The effectiveness of palonosetron has also been supported by studies conducted in solid tumors, as well as in blood cancers, demonstrating that patients receiving palonosetron had significantly lower CINV event rates than patients receiving other 5-HT₃-RAs, and that palonosetron can be safely and effectively administered to patients receiving chemotherapy regimens administered over multiple days per cycle.^12-15

Although the effectiveness of the older 5-HT₃-RA agents (ie, ondansetron, dolasetron, and granisetron) in preventing emesis in the acute phase (0-24 hours after chemotherapy administration) has been well documented, delayed CINV (2-5 days after chemotherapy adminis­tration), particularly nausea, continues to pose clinical (ie, including negative impact on quality of life)¹⁶ and economic burdens for patients with cancer.

Uncontrolled delayed CINV has been defined as nausea and/or vomiting or a diagnosis of dehydration made during an office visit, emergency department visit, or hospitalization.^4,14 The rates of uncontrolled CINV have been estimated to be as high as 28%,⁴ and uncontrolled CINV has been associated with 25% to 50% of patients delaying or refusing chemotherapy.¹⁷ Up to 82% of women receiving MEC or HEC can experience delayed nausea.¹⁸ Even if patients do not experience CINV in the first 24 hours of chemotherapy administration, delayed CINV affects activities of daily life in 23% of patients.^18-20 Uncontrolled CINV has been shown to be associated with increased resource utilization and costs, particularly for patients receiving MEC or HEC.^21,22 In a study assessing CINV costs for the first cycle of a MEC or HEC regimen, 64% of CINV-associated visits included an inpatient visit and 26% included an outpatient visit, with the mean cost of a CINV visit calculated to be $5299 (standard deviation [SD], $6639).²¹ Another study has estimated the average daily cost of CINV to be approximately $1850.22 These costs further show the need to establish control of CINV at the first chemotherapy cycle.

Because CINV in the delayed phase is still a problem for patients receiving chemotherapy, the evidence for the effectiveness of palonosetron, and the increasing pressure to contain healthcare costs, we conducted this study to evaluate the clinical and economic impacts of delayed CINV in patients who initiated therapy with palonosetron and maintained therapy with palonosetron versus patients who initiated therapy with an older 5-HT₃-RA and received maintenance therapy with that older agent throughout their chemotherapy cycles.

Methods A retrospective database analysis was conducted utilizing the OptumInsight database from the years 2005 through 2011. The OptumInsight database covers millions of lives, with a distribution of 96% of patients being commercially insured and 4% of patients covered by Medicaid. Pharmacy and medical claims are available from healthcare providers, facilities, and pharmacies. Information on individual physician visits, medical procedures, hospitalizations, medications, and laboratory tests are available, with charged amounts reported for the services rendered.

Study Population
Patients with cancer were initially identified based on an International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) diagnosis code for any type of cancer. Patients receiving initial MEC, HEC, low emetogenic chemotherapy, or a minimally emetogenic single-day chemotherapy regimen in conjunction with a 5-HT3-RA (ie, dolasetron, granisetron, ondansetron, or palonosetron) were subsequently eligible for study inclusion. All emetogenic levels of chemotherapy were included as part of the initial inclusion criteria to ensure that patients were chemotherapy naïve.

The index date was defined as the first date of the administration of chemotherapy and 5-HT₃-RA, and patients were classified into 1 of 4 treatment cohorts based on the 5-HT₃-RA prescribed on the index date. All patients were required to have 12 months of continuous enrollment; information from the 6 months before the index date was used to capture baseline information on patients, and information from the 6 months after the index date was used to assess for CINV or CINV-related utilization and costs (Figure 1).

Figure 1

Patients included in the analysis were required to be chemotherapy naïve. Patients who had a claim for a previous antiemetic 5-HT₃-RA or for chemotherapy during the preindex period were excluded. Patients receiving multiday chemotherapy were also excluded. Once patients received initial chemotherapy, they were required to remain on the same level of emetogenicity (ie, MEC or HEC), as well as maintain therapy with the same 5-HT₃-RA agent throughout the entire analysis period. Patients who switched their 5-HT₃-RA agent were excluded from the study at that particular point during the observation; however, their data were accumulated and included in the final analysis.

Outcomes
The clinical outcomes that were measured in the analysis included unadjusted rates of delayed CINV for cycles 1 to 6 in the overall study population and by specific 5-HT₃-RA cohort. Delayed CINV was defined as a primary or secondary diagnosis of nausea, vomiting, or de­hydration (ICD-9-CM: 787.0, 787.01, 787.02, 787.03, 276.5, 276.51, 276.52) on days 2 to 5 after chemotherapy, or by the use of rescue antiemetic therapy after the administration of chemotherapy. Rescue medications were identified by J-codes or by National Drug Codes and consisted of olanzapine, promethazine, haloperidol, prochlorperazine, lorazepam, metoclopramide, and/or intravenous antiemetic administration of dolasetron, gra­nisetron, ondansetron, or palonosetron.¹⁰ Any administration of rescue medications, antiemetic medications, or hydration procedures on the day of chemotherapy administration was not considered to be for delayed CINV.

For the purpose of calculating delayed CINV rates for chemotherapy in cycles 2 to 6, the calculations were based on patients who experienced CINV in the previous chemotherapy cycle (ie, breakthrough nausea/vomiting or treatment failure), were maintained on the same 5-HT₃-RA agent, and had chemotherapy with the same level of emetic potential. For example, a patient who remained in this analysis at cycle 5, experienced breakthrough CINV in cycles 1 to 4, received the same 5-HT₃-RA, and had the same level of emetogenic chemotherapy (eg, HEC) in cycles 1 to 5. Patients who did not meet the criteria were dropped from the CINV rate calculation. In addition to CINV rates, the adjusted odds ratios (ORs) for CINV were also calculated for each 5-HT₃-RA cohort.

The economic outcomes related to CINV were also collected and were calculated by cycle. The charges for delayed CINV were calculated as a mean for each patient, and then by aggregate for the entire population remaining in the analysis by cycle. The charges in the model included physician, outpatient facility, inpatient facility, pharmacy, and “other” medical costs. The charges were then entered into a model representing an overall random sample of 1000 patients at cycle 1. A charge per patient was calculated and was used to determine an average charge for all patients in each 5-HT₃-RA cohort based on the percentage of patients in each cycle who experienced delayed CINV.

As was the case for the CINV rate calculation, patients without CINV in the previous cycle, patients who switched 5-HT₃-RA therapy, and patients who changed the level of chemotherapy emetogenicity were excluded from subsequent calculations. Palonosetron was used as a baseline marker, and all patients remained in the analysis until they dropped off, based on the rates calculated from our analysis. The costs were accumulated for this population over 6 cycles.

Statistical Analysis Descriptive statistics for patient and treatment characteristics were calculated. Comparisons of baseline and treatment characteristics were conducted using t-tests, nonparametric Wilcoxon rank-sum tests, and chi-square tests. Logistic regression was utilized to calculate adjusted ORs for experiencing CINV while controlling for age, sex, Charlson Comorbidity Index (a higher score indicating higher clinical disease burden), type of chemotherapy regimen (HEC vs other regimens), additional antiemetic therapy (eg, with dexamethasone and aprepitant), and specific 5-HT₃-RA.

Results
A total of 26,974 patients met the inclusion criteria for the study. The overall average age was 55.7 years, with patients in the dolasetron cohort having the oldest average age of 57.9 years (P <.001). Patients receiving palonosetron were younger, with an average age of 55.3 years. The majority of patients across all cohorts were female, with 71% of patients who were receiving palonosetron being female. Preindex comorbidity scores were lowest in the palonosetron cohort (4.6) and highest in the dolasetron cohort (4.9; Table 1).

Table 1

Most patients (72%) had a cancer diagnosis for a single site. Of these patients, 53% had a diagnosis of breast cancer, 20% had a diagnosis of lung cancer; the remainder of patients were split between ovarian, colon, and other cancers. More patients in the palonosetron cohort received an HEC regimen than any other type of chemotherapy, which was in contrast to the other 5-HT₃-RA groups, where MEC was the predominant regimen (Table 2).

Table 2

Dexamethasone was consistently used in the first cycle for all treatment groups, with the palonosetron cohort having the highest (93.1%) utilization rate. In addition, aprepitant was most often used in the palonosetron cohort, with 10.7% of patients receiving aprepitant (Table 2).

As shown in Table 2, the overall rate for delayed CINV at cycle 1 was 15.6%. When stratified by 5-HT₃-RA cohorts, delayed CINV was lowest (15%) in the palonosetron cohort, followed by ondansetron (16.9%), granisetron (17%), and dolasetron (17.3%).

The rates of delayed CINV increased for each subsequent chemotherapy cycle when evaluating patients who experienced CINV in the previous chemotherapy cycle. The delayed CINV rates increased by 21.8% from cycle 1 to cycle 2, by 31.7% from cycle 2 to cycle 3, they began to level off by cycle 4, and then increased slightly (5.7%) by cycle 6 (Figure 2).

Figure 2

When evaluating delayed CINV rates by the specific 5-HT3-RA therapy, patients initiating therapy with palonosetron had lower delayed CINV rates throughout all 6 cycles of chemotherapy. These numbers are dependent on the percentage of patients experiencing CINV in the previous chemotherapy cycle. Ondansetron was the next lowest cohort, with dolasetron and granisetron demonstrating intermittent results from cycle to cycle (Figure 3). The type of chemotherapy that patients with CINV received is reported in Table 3.

Figure 3

Table 3

A multivariate regression analysis comparing the individual 5-HT3-RA agents to palonosetron demonstrated higher odds of delayed CINV in the second cycle (ondansetron: OR, 1.41; 95% confidence interval [CI], 1.14-1.74; P <.002; granisetron: OR, 1.70; 95% CI, 1.39-2.08; P <.001; dolasetron: OR, 1.65; 95% CI, 1.27-2.15; P = .002). This trend continued for all agents through cycle 6; however, not all ORs were statistically significant (Table 4).

Table 4

With regard to economic outcomes, physician charges constituted the largest component of overall pharmacy and medical charges. As a result, medical costs constituted the largest component of the total costs. For cycle 1, the average total cost per patient, regardless of CINV status, was $5902 (SD, $4920), including $5705 attributable to medical costs and $197 attributable to pharmacy costs. Similar trends occurred for subsequent cycles. The unadjusted mean charges are reported for all patients and for patients who did and did not experience CINV in Table 5.

Table 5

As expected, patients experiencing CINV incurred higher charges. Based on our model of 1000 patients, patients receiving palonosetron had the lowest charges associated with delayed CINV over 6 cycles of chemotherapy. As shown in Figure 4, using palonosetron as a baseline measure, patients receiving granisetron incurred the highest charges over 6 cycles. Over 6 cycles, ondansetron cost an additional $126,775 compared with palonosetron; granisetron an additional $169,838 versus palonosetron; and dolasetron an additional $148,960 (Figure 4).

Figure 4

Discussion
The overall rates of delayed CINV increased in subsequent cycles of chemotherapy for patients who had experienced CINV in the previous chemotherapy cycle and remained on the same 5-HT₃-RA therapy throughout the duration of the study period. Among the different 5-HT₃-RA cohorts, patients receiving palonosetron had lower rates of CINV and associated charges, a trend which was consistent across all 6 cycles of chemotherapy. These results are congruent with findings from other studies evaluating palonosetron for delayed CINV. Real-world studies have demonstrated that patients receiving palonosetron have decreased CINV event rates compared with patients receiving older 5-HT₃-RAs.^4,12,13

In their study, Balu and colleagues predicted an overall 13.7% decrease in CINV rates for patients treated in the clinic setting and a 12.5% decrease in CINV rates for patients in the hospital outpatient setting receiving palonosetron as prophylaxis per cycle of chemotherapy compared with patients receiving an older 5-HT₃-RA.¹² Patients in that study who received palonosetron were younger, and were more likely to be female, white, to receive an HEC regimen, and to have breast or lung cancer, many of which were similar patient demographics to the patients included in our study.¹² Several of these characteristics (ie, younger age, female sex, treatment with HEC) place patients at increased risk for the development of CINV. Of note, a higher proportion of these patients who are at greater risk for the development of CINV were administered palonosetron in this claims analysis.¹²

In another study, Lin and colleagues evaluated patients with a diagnosis of breast or lung cancer receiving an MEC or HEC regimen who initiated therapy with palonosetron and maintained therapy on palonosetron versus patients who initiated therapy with an older 5-HT₃-RA and later switched to palonosetron.¹³ Patients who received palonosetron from cycle 1 and maintained palonosetron therapy experienced a lower incidence of CINV and lower resource utilization associated with CINV than patients initiating therapy with an older 5-HT₃-RA and later switching to palonosetron. Patients in the palonosetron cohort had 22% to 51% fewer 5-HT₃-RA claims and fewer CINV events (3.5% vs 5.5% in the breast cancer cohort, 9.5% vs 12.8% in the lung cancer cohort receiving carboplatin, and 16.4% vs 21.7% in the lung cancer cohort receiving cisplatin). In addition, patients in the palonosetron cohort had a lower risk for CINV events (OR, 0.62 for patients with breast cancer; OR, 0.71 for patients with lung cancer).¹³

In our study, we took a slightly different approach than that used in the study by Lin and colleagues: patients in our study did not switch 5-HT₃-RA therapy, allowing for an insight into the effects of therapy in subsequent chemotherapy cycles for patients who failed antiemetic therapy in cycle 1 and continued to experience breakthrough CINV in cycles 2 to 6 but did not switch 5-HT₃-RA therapy. Evaluating the rates of CINV in this manner highlights the potential advantages of utilizing palono­setron from the initiation of chemotherapy.

Tina Shih and colleagues evaluated working-aged patients with cancer and determined that, despite the use of 5-HT₃-RAs, uncontrolled CINV is still problematic for approximately 28% of patients.⁴ The study demonstrated the need to control CINV from cycle 1 to curb resource utilization and the associated costs. That study included data before the advent of palonosetron and aprepitant, but the authors conducted a sensitivity analysis to determine the threshold at which the benefit of a newer antiemetic would outweigh the cost of the agent.⁴ Our study results support the use of newer agents (specifically palonosetron). The higher success rate in the delayed setting at cycle 1 resulted in fewer patients experiencing CINV in subsequent chemotherapy cycles. Even the subset of patients that experienced breakthrough CINV in the previous chemotherapy cycle subsequently treated with palonosetron exhibited favorable outcomes with lower rates of CINV throughout the remainder of cycles.

The cost-effectiveness of palonosetron is shown by the economic results of our analysis. In our random sample of 1000 patients for each 5-HT₃-RA cohort, patients receiving palonosetron would have incurred a lower cost of $126,000 to $170,000 in CINV-related charges compared with patients in the older 5-HT₃-RA cohorts. This is an important consideration given the economic implications of uncontrolled CINV.

Tina Shih and colleagues determined that the average monthly medical costs for patients with uncontrolled CINV were 29.79% higher than those for patients whose CINV was being controlled, even after adjusting for demographic, socioeconomic, and clinical characteristics.⁴ This difference translated to approximately $1280 in 2007 dollars.⁴

In addition, Burke and colleagues calculated the CINV-related costs for the first cycle of an MEC or an HEC regimen and found that the mean cost of a CINV-­related visit was $5299 (SD, $6639).²² Our study further confirms the value of preventing CINV early in chemotherapy treatment, because the cohort with lower rates of CINV (in our study patients receiving palonosetron) incurred fewer charges over the 6 cycles of chemotherapy.

Limitations
Several limitations associated with this analysis merit disclosure. Because this was a claims analysis, it is possible that not all cases of CINV were captured. However, severe cases of CINV were likely captured, because patients would have incurred resource utilization for treatment prompting a medical claim.

Furthermore, drug therapy was also evaluated for rescue medications utilizing ICD-9 codes and National Drug Codes, which would signal a CINV event. It should be acknowledged that patients may receive a supply of rescue medications for as-needed use at home. In these instances, delayed CINV rates may not be captured; therefore, our estimates may actually underestimate the incidence of delayed CINV.

Finally, the study population consisted primarily (96%) of commercially insured patients and, therefore, may not apply in the same way to other populations; this should be considered when generalizing this information to other patient populations.

Conclusions
Although all 5-HT₃-RA agents are effective in preventing CINV, the evidence has shown that there are differences in efficacy, as well as cost-effectiveness, between the older agents and palonosetron, the newer 5-HT₃-RA agent. Based on the current analysis, delayed CINV rates increased subsequent to the first chemotherapy cycle for patients with CINV who maintained therapy with the same 5-HT₃-RA from one cycle to the next. For patients who initiated therapy and maintained therapy with palonosetron, the incidence of delayed CINV in the first cycle and in subsequent cycles was lower than in the patients receiving one of the older 5-HT₃-RA agents. Similar trends were found with regard to resource utilization and associated costs. Selecting the most appropriate 5-HT₃-RA during the first cycle of chemotherapy is imperative, because the risk for developing CINV in subsequent chemotherapy cycles increases if CINV is not prevented at the time of chemotherapy initiation. If CINV is not controlled early, palonosetron can still exhibit benefits in subsequent cycles compared with the older 5-HT₃-RAs. The information gleaned from this analysis can assist healthcare providers with treatment selection as well as guide healthcare decision makers with formulary decisions.

Acknowledgment
Meg Franklin, PharmD, PhD, of Franklin Pharmaceutical Consulting, LLC, assisted with the writing and preparation of the manuscript.

Funding Source
Funding for this study was provided by Eisai, Inc.

Author Disclosure Statement
Dr Faria is an employee of, Mr Li is a consultant to, and Dr Nagl is an employee of Eisai, Inc. Dr McBride reported no conflicts of interest.

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