The Impact of 5-HT3RA Use on Cost and Utilization in Patients with Chemotherapy- Induced Nausea and Vomiting: Systematic Review of the Literature

Chemotherapy-induced nausea and vomiting (CINV) is an adverse effect of cancer treatment. It may occur within a few minutes of or up to 24 hours after the administration of chemotherapy (ie, acute CINV), or it may occur more than 24 hours after treatment (ie, delayed CINV). CINV may last up to 7 days.^1-7 Although there are several patient-specific factors that place patients at an increased risk for developing CINV (eg, female sex, low consumption of alcohol, history of motion or morning sickness, age under 50 years, previous CINV), the most contributory risk factor is the emetogenic potential of the chemotherapy regimen itself.⁸

More than 90% of patients undergoing highly emetogenic chemotherapy (HEC) will experience emesis without antiemetic prophylaxis, and 30% to 90% of those undergoing moderately emetogenic chemotherapy (MEC) will vomit without the prophylactic administration of antiemetics.⁸ From 10% to 30% of the patients receiving low emetogenic risk chemotherapy (LEC), and <10% of patients receiving minimal emetogenic risk chemotherapy (MinEC), will experience emesis without the administration of antiemetics.^3,6,7,9 The dose, frequency, and length of administration, as well as the combination of agents may impact the emetogenicity of the chemotherapy.⁷

Poorly controlled CINV may lead to nutrient depletion, reduced functional ability, diminished quality of life, or the premature discontinuation of chemotherapy.^1-4,6,7,9 The use of prophylactic antiemetic medications in patients undergoing HEC may reduce the incidence of CINV to as low as 30%.⁷ A multidrug regimen containing a 5-hydroxytryptamine receptor antagonist (5-HT₃RA) is the standard approach for CINV prophylaxis.⁷ Drugs in this category include dolasetron mesylate, granisetron, ondansetron, palonosetron, and tropisetron, with palonosetron recommended as the preferred 5-HT₃RA for CINV prophylaxis with MEC by the guidelines of the National Comprehensive Cancer Network (NCCN), the Multinational Association of Supportive Care in Cancer/Economic Society for Medical Oncology (MASCC/ESMO), and the American Society of Clinical Oncology (ASCO).^5,7,10

Secondary rescue medications are used to treat breakthrough CINV among patients who have received prophylaxis.⁷ These medications may include metoclopramide, lorazepam, diphenhydramine, olanzapine, prochlorperazine, or dexamethasone.

CINV increases direct costs (eg, medication, office visits, or hospitalizations) and indirect costs (eg, missed work).^3,4,9 The effective prevention of CINV may reduce these costs. The clinical and economic impact of CINV underscore the importance of achieving CINV prophylaxis.^3,4,9 Palonosetron—which has greater binding affinity and a longer half-life than the other 5-HT₃RAs, binds allosterically, stimulates receptor internalization, demonstrates positive cooperativity, and cross talks with the neurokinin (NK)-1 signaling pathway—prevents both acute and delayed CINV more effectively than the other 5-HT₃RAs.^7,11-14

The extent to which the clinical benefit of 5-HT₃RAs translates into reduced costs or utilization of healthcare services among patients with CINV has been shown in individual studies for subsets of outcomes,^3,15 but no summary of the literature exists. We conducted a systematic literature review of published research on the healthcare costs and utilization associated with the use of 5-HT₃RAs for the prevention of CINV in patients receiving chemotherapy, with the goal of comparing palonosetron with the other 5-HT₃RAs.

Methods
This systematic review of the literature was conducted according to the Cochrane Collaboration model.^16,17 The searches were done in PubMed and in 3 additional databases of the National Institute for Health Research Centre for Reviews and Dissemination (NIHRCRD), including the Database of Abstracts of Reviews of Effects, the National Health Service Economic Evaluation Database, and the Health Technology Assessment Database. We also searched conference abstracts that were presented at meetings of the Academy of Managed Care Pharmacy, ASCO, International Society for Pharmacoeconomics and Outcomes Research, and MASCC. Searches for articles were conducted on July 12, 2012 (PubMed) and July 5, 2012 (NIHRCRD). The searches of conferences covered the years 2010, 2011, and 2012. The searched terms included the medical subject headings, subheadings, and key words “5-HT₃RAs,” “dolasetron mesylate,” “granisetron,” “ondansetron,” “palonosetron,” “tropisetron,” “Anzemet,” “Kytril,” “Zofran,” “Aloxi,” “Navoban,” “cost,” “cost analysis,” “economics,” “utilization,” “CINV,” “emesis,” “nausea,” and “vomiting.”

We excluded full-length articles that were published before 1997 and were not in the English language, or those that did not report data on human subjects, CINV, 5-HT₃RAs, pharmacologic treatment, or cost and utilization. If a study was duplicated as a full-length article and a conference abstract, only the article was retained for review.

Data abstracted from accepted articles included study metadata, design, patients, treatments, and healthcare cost and utilization. The cost data included pharmacy costs (eg, acquisition/administration of 5-HT₃RAs, acquisition/administration of rescue medication), medical costs (eg, outpatient, inpatient), total healthcare costs (eg, total pharmacy, total medical). The utilization data included the rates of rescue medication use, outpatient service use, inpatient service use, and any healthcare resource use (eg, medication, outpatient, or inpatient use).

A single reviewer abstracted the articles. As part of the quality assurance process, all data were independently reabstracted, all inconsistencies were discussed, and final determinations were recorded in the review. The Oxford Centre for Evidence-Based Medicine’s (OCEBM) level of evidence scale was used to assess quality of evidence and to assign a grade of 1 to 5 to each of the included studies, where 1 indicated a study with the strongest scientific basis for support of conclusions and 5 the weakest (eg, expert opinion).¹⁸

Randomized controlled trials (RCTs) were assigned a quality score using the Jadad scale, which assigns points on a scale of 0 to 5 based on a study’s use of randomization, and blinding and on its description of withdrawals and dropouts from participation.¹⁹ The costs were directly abstracted from studies, and no currency conversions or inflation adjustments were applied in this review.

Results
The initial search identified 434 studies, including 414 journal articles and 20 conference abstracts (Figure). Of these, 29 were duplicates, 212 were ineligible after screening titles and abstracts, and 161 were ineligible after screening the full articles. A total of 32 studies were included in this review, of which 21 were full-length articles and 11 were conference abstracts.

The 32 studies were published between 1998 and 2012 and reported data from 1995 to 2011 (Appendix A).^{1,3,4,6,9,15,20-45} Of the 32 studies, 19 were conducted in the United States. A total of 7 studies were RCTs; 8 were nonrandomized, prospective studies; 14 were retrospective cohort analyses; and 3 were cost-efficacy analyses. Sample sizes ranged from 36 patients⁴³ to 11,974 patients.³⁰ The OCEBM levels of evidence ranged from 1b to 3b for all reviewed studies, and Jadad scores ranged from 2 to 5 for the 7 RCTs.

Description of Included Studies
A variety of indications for chemotherapy were represented in the studies, including breast, lung, head, neck, ovarian, gastrointestinal, colorectal, urogenital cancers, lymphoma, leukemia, and bone marrow transplant (Appendix A). Two studies included only patients with breast cancer,^21,37 and in 7 other studies, the majority (≥50%) of patients had breast cancer.^{1,6,22,28,31,32,38} Chemotherapy treatment protocols (single or multiday) ranged from 1 to 5 days. A total of 9 studies included solely HEC regimens, 9 included only MEC regimens, and 13 included some combination of chemotherapy (eg, HEC, MEC, LEC, and MinEC).

The studies examined single and multiple 5-HT₃RAs, alone and in combination with other medications. Of the 32 studies, 25 included palonosetron. Dosing schedules ranged from a single intravenous (IV) administration of a 5-HT₃RA to courses of IV and oral formulations given over several days. CINV prophylaxis was administered with and without adjunctive aprepitant and dexamethasone. Rescue medications included metoclopramide, lorazepam, diphenhydramine, prochlorperazine, and dexamethasone.

A total of 14 studies reported cost data, and 25 reported data on utilization (Appendix A). Costs were reported in US dollars (7 studies), Euros (5 studies), and Canadian dollars (2 studies), based on a variety of sources and in several ways. The medication acquisition costs were from government schedules, prices paid by other payers, or from average wholesale prices. Medical costs were reported by treatment setting (outpatient, inpatient, or in aggregate) and in a variety of ways, such as mean cost per office visit and cost per cycle. The inpatient costs, either hospital admissions or emergency department visits, were stated per event (eg, per admission), per chemotherapy cycle, and per patient.

Healthcare Costs Associated with 5-HT₃RA Use in the United States
A total of 7 US studies reported costs associated with the use of 5-HT₃RAs for CINV, although only 4 studies compared the costs associated with the use of palonosetron and other drugs of this class (Table 1). Two studies reported the cost of 5-HT₃RA prophylaxis acquisition and rescue medication, 3 studies reported the cost of outpatient or inpatient medical services, and 6 studies reported the total pharmacy or total treatment costs.

Avritscher and colleagues reported the 5-HT₃RA prophylaxis acquisition costs of $49.74 per cycle for ondansetron alone, $207.20 for palonosetron alone, $324.51 for ondansetron when administered with aprepitant, and $482.46 for palonosetron when administered with aprepitant.²¹ Another study reported the cost of acquisition for ondansetron, which was $1651 for the IV formulation and $539 for the oral formulation compared with $684 for oral granisetron.²⁵ Avritscher and colleagues reported the cost of rescue medications as $35.25, regardless of the specific 5-HT₃RA used.²¹ The previous study also reported a rescue medication cost of $102 among patients receiving oral ondansetron, $96 for IV ondansetron, and $86 for patients receiving oral granisetron.²⁵

A retrospective study of patients receiving HEC reported daily outpatient costs for CINV events of $1216 per cycle in patients receiving palonosetron compared with $1356 for patients taking other 5-HT3RAs.¹⁵ A more recent retrospective study reported daily outpatient costs for CINV events for patients receiving palonosetron prophylaxis were approximately $1048 compared with $1339 when taking other 5-HT₃RAs.²⁴ Balu and colleagues also reported mean emergency department service costs for CINV events of $1664 for patients receiving palonosetron compared with $1890 for patients receiving other 5-HT₃RAs, and mean inpatient costs of $2581 for the palonosetron cohort compared with $2671 for other 5-HT₃RAs.¹⁵ For patients receiving any 5-HT₃RA, Avritscher and colleagues reported a mean cost of $60.30 per clinic office visit for a CINV event and $5237 per hospitalization.²¹

Fox-Geiman and colleagues reported the total pharmacy cost, including prophylaxis, rescue medication, and drug administration, to be $641 per cycle for patients receiving oral prophylaxis with ondansetron, $1747 for IV ondansetron, and $770 for oral granisetron.²⁵ A recent study reported a mean total pharmacy cost of $2129 in patients with CINV taking one of several 5-HT₃RAs.³¹

The total treatment costs, including all healthcare charges for prophylaxis and the treatment of CINV events, were reported in 5 studies.^{15,21,31,33,34} Two studies reported that palonosetron when used alone was less costly than any other 5-HT₃RAs.^15,33 Avritscher and colleagues modeled the direct medical costs of ondansetron-based multiple drug therapies and palonosetron-based multiple drug therapies over 4 cycles of chemotherapy and reported that treatment costs with palonosetron-based regimens were higher compared with ondansetron-based regimens.²¹ A recent study of patients undergoing HEC or MEC and using 5-HT₃RAs reported total CINV-related treatment costs (ie, medical and pharmaceutical claims) of $4816, although the costs for palonosetron alone were not reported.³¹ A study of commercially insured patients who were primarily treated with palonosetron (72%) reported a treatment cost of $1604 per cycle for a patient experiencing a CINV event (ie, 5-HT₃RA infusion or medical claims with CINV diagnosis), but the study did not report costs for palonosetron alone.³⁴

Healthcare Utilization Associated with 5-HT3RA Use in the United States
In all, 16 studies reported data on healthcare utilization related to the use of 5-HT₃RAs for CINV in the United States, of these 12 reported rescue medication use, 2 reported outpatient medical service use, and 6 reported inpatient service use (Table 2).

Of the 12 studies, 10 that reported the frequency of rescue medication use in the United States specifically presented comparative results between patients receiving palonosetron and patients receiving other 5-HT₃RAs. Of these 10 studies, 8 found lower rescue medication use among patients receiving palonosetron. One RCT reported lower rescue medication use in patients receiving palonosetron compared with patients receiving ondansetron (6% vs 11%, respectively).⁴¹ Four retrospective studies also reported lower rescue medication utilization rates in those treated with palonosetron compared with ondansetron (24% vs 67%, respectively³; 28% vs 83%, respectively⁴; 8% vs 11%, respectively³⁵; and 14% vs 24%, respectively³⁶). Knoth and colleagues also reported higher rescue antiemetic rates in Medicaid patients with cancer who received granisetron (20%) and dolasetron (20%) compared with palonosetron (8%).³⁵ Another retrospective study of commercially insured patients also reported higher rescue medication needs in patients given granisetron (27%) and dolasetron (31%) compared with palonosetron (14%).³⁶ Three other retrospective studies reported rescue medication needs in patients treated with palonosetron versus with multiple 5-HT₃RAs (7% vs 12%, respectively,³² 16% vs 30%, respectively,³³ and 35% vs 35%, respectively⁶). The rates of rescue medication use were 61% in patients receiving ondansetron and 56% in patients receiving palonosetron in one cost-efficacy analysis study.²¹

Of 10 outpatient or inpatient utilization rate comparisons reported in 6 studies, 8 comparisons were lower among patients receiving palonosetron prophylaxis than in patients receiving other 5-HT3RAs, and 2 comparisons had equivalent rates between the palonosetron and other 5-HT₃RA cohorts (Table 2). Two studies reported lower rates of physician office visits (5% vs 10%, respectively) and outpatient service use (8% vs 10%, respectively) related to CINV among patients receiving palonosetron compared with patients receiving ondansetron.^21,45

Patients receiving palonosetron had lower or equivalent rates of outpatient service use compared with patients treated with ondansetron: the rates of hospitalization were approximately 0.2% versus approximately 0.4%, respectively,²¹ whereas the rates of hospital readmission (which are related to CINV from days 1-7 after the last round of chemotherapy) were 1% versus 1%, respectively,⁴ and 0% versus 5%, respectively.⁴⁵ Yeh and colleagues reported the same rate (0%) of emergency department visits related to CINV in patients receiving palonosetron and in patients receiving ondansetron.⁴⁵ In comparing patients treated with palonosetron with patients treated with any other 5-HT₃RA, fewer patients in the palonosetron group had hospitalizations (4% vs 6%, respectively; 10% vs 14%, respectively; and 16% vs 23%, respectively³⁰) and emergency department or hospital admission events (7% vs 10%, respectively³⁹).

Healthcare Cost Associated with 5-HT₃RA Use in Europe and Canada
A total of 7 studies reported the costs associated with the use of 5-HT₃RAs for CINV in Europe and Canada. Of these studies, 6 reported the cost of 5-HT₃RA acquisition, 5-HT₃RA administration, or rescue medication; 3 studies reported the cost of outpatient or inpatient medical services; and 5 studies reported the total pharmacy or total treatment costs (Appendix B).

Only 1 study reported costs for the use of palonosetron.²⁶ The acquisition costs of 5-HT₃RAs and rescue medication costs varied by study. For example, 1 study reported the acquisition cost of ondansetron ranged from €17.90 to €57.75, tropisetron from €14.80 to €23.59, and granisetron from €26.16 to €41.60^,22 whereas another study reported the costs for rescue medication ranged from €7.22 for all cycles to €11.20 for cycles with CINV per treatment cycle per patient.⁹ The outpatient and inpatient medical costs varied across the studies. For example, the outpatient medical costs for CINV treatment ranged from €0.23 for medical consultation in patients treated with tropisetron²² to €9.28 for outpatient care in patients treated with ondansetron.⁴⁰ The inpatient medical costs varied from €0.43 for emergency department admission per cycle²² to €151.86 per patient for hospitalization.⁴⁰ Of the 5 studies that reported the total costs, only 1 study reported the costs associated with the use of palonosetron.²⁶ There were substantially lower total pharmacy costs related to prophylaxis with palonosetron compared with tropisetron: €107.25 versus €410.50, respectively.²⁶

Healthcare Utilization Associated with 5-HT₃RA Use in Europe and Canada
A total of 9 studies reported data on healthcare utilization related to the use of 5-HT₃RAs for CINV in Europe or in Canada, and, of these, 8 studies reported utilization associated with the use of palonosetron (Table 3). The use of rescue medication varied widely (3%-40% of patients), considering which 5-HT₃RA was used, treatment time relative to chemotherapy, and treatment duration, dosage, and administration route.

Similar to US studies, the rates of rescue medication use were lower for palonosetron versus for other 5-HT₃RAs: 20% vs 23%, respectively²⁰; 9% vs 12%, respectively²⁶; 16% vs 24% or 19% vs 27%, respectively²⁸; and 20% vs 40%, respectively.⁴² The use of outpatient services, including medical consultations and hospital visits, ranged from 2% (tropisetron) to 11% (multiple 5-HT₃RAs) and the use of inpatient services, including emergency department visits and hospitalizations, ranged from 0% (ondansetron or granisetron) to 1% (ondansetron, tropisetron, granisetron, or multiple 5-HT₃RAs), but no rates were reported for palonosetron in these studies.^9,22

Discussion
Our literature review shows that CINV prophylaxis with palonosetron compared with ondansetron is generally associated with higher acquisition costs, a finding supported by the ASCO guidelines that reported a higher total cost per treatment cycle for palonosetron than for granisetron, ondansetron, and dolasetron.¹⁰ However, palonosetron is generally associated with lower use of rescue medications and outpatient and inpatient services compared with ondansetron or other 5-HT₃RAs.

In Europe and in Canada, the total pharmacy costs and rescue medication use are lower for patients treated with palonosetron. Overall, the healthcare utilization results from Europe and Canada are consistent with results from the United States. This study highlights the use of palonosetron as a standard treatment, which may lead to the reduced utilization of rescue medications and healthcare services for CINV, and possibly result in subsequent cost-savings related to medical outpatient and inpatient services.

A recent comprehensive review of efficacy data suggests that patients who receive palonosetron experience less nausea, both acute (relative risk [RR], 0.86; 95% confidence interval [CI], 0.76-0.96; P = .007) and delayed (RR, 0.82; 95% CI, 0.75-0.89; P <.001), and less acute vomiting (RR, 0.76; 95% CI, 0.66-0.88; P = .002) and delayed vomiting (RR, 0.76; 95% CI, 0.68-0.85; P <.001).¹¹

The NCCN recommends palonosetron as the preferred 5-HT₃RA for patients undergoing HEC.⁷ Palonosetron is also recommended by the NCCN, MASCC/ESMO, and ASCO guidelines as the preferred 5-HT₃RA for CINV prophylaxis with MEC,^5,7,10 and is the preferred 5-HT₃RA according to the MASCC/ESMO guidelines for anthracycline combined with cyclophosphamide chemotherapy when an NK₁ receptor antagonist is not available.⁵

The utilization data evaluated in the reviewed studies support the hypothesis that patients managed with palonosetron use fewer outpatient, emergency department, and inpatient care services than patients who receive other 5-HT₃RA agents. The utilization of medical services related to CINV may have a role as an important metric for plans, providers, and patients in identifying the appropriate therapy for CINV prophylaxis.

This review focused on 2 specific outcomes—medical costs and utilization—but the evidence we report has implications for patients in terms of quality of life, indirect costs, and treatment discontinuation resulting from CINV. Studies have shown that CINV adversely impacts quality of life of patients with cancer.⁴⁶ Patients with cancer have rated being free from CINV as one of the most favorable health states after perfect health and complete remission.⁴⁷ Less quantifiable but still impor­tant, indirect costs associated with CINV may include lost productivity and patient and family anxiety.

Studies have previously documented the impact of CINV on indirect costs in terms of reduced productivity or workdays lost.^9,48,49 A Canadian study found that indirect costs accounted for up to 66% of the total cost of CINV among 72 patients,⁴⁹ whereas a US study reported that 23% of their patients were not able to work as a result of emesis.⁴⁸ CINV prophylaxis may also be important in avoiding chemotherapy discontinuation as a result of CINV complications. The NCCN antiemesis guidelines cite research that suggests that compliance with therapy—in particular, infusion therapy appointments—is decreased in patients who experience nausea and vomiting.^7,50

Several independent studies have demonstrated the benefits of compliance to antiemetic guidelines for CINV prophylaxis before single-day HEC or MEC.^51-53 A recent prospective observational study of oncology practices in the United States reported the incidence of no CINV was significantly higher in the guideline-consistent CINV prophylaxis (GCCP) cohort compared with the guideline-inconsistent CINV prophylaxis (GICP) cohort over 5 days postchemotherapy (53.4% vs 43.8%, respectively; P <.001).⁵² The adjusted odds of no CINV in the GCCP group were 1.31 (95% CI, 1.07-1.69).⁵²

An earlier prospective observational study, which was conducted in 8 European countries, reported a higher complete response (no emesis and no use of rescue therapy) rate in a GCCP cohort (59.9%) compared with in a GICP cohort (50.7%; P = .008).⁵¹ After controlling for a variety of confounding factors, patients in the GCCP cohort had 1.43 times the odds of complete response (95% CI, 1.04-1.97; P = .027) compared with patients in the GICP cohort.⁵¹

Despite the wide availability of guidelines on the prevention of CINV and the worldwide evidence of favorable outcomes with higher guideline compliance, adherence to and implementation of treatment recommendations in antiemetic guidelines on CINV are often suboptimal.^51-53 Studies indicate that more effective clinical uptake of guidelines, developed by consensus opinions of international experts published by the MASCC, ASCO, and the NCCN, for the prevention of CINV improve patient outcomes, including the reduced incidence of CINV and healthcare visits to manage CINV and improved quality of care and cost-savings.^51-53

Strengths and Limitations
The strength of this research lies in its comprehensive review and in its synthesis of global literature that is published in peer-reviewed journals and is presented at professional congresses.

This study also has limitations. To conduct a comprehensive review, we did not exclude studies that used relevant outcomes of interest (eg, costs, utilization) as model inputs.^21,38,40

The studies included in this review varied in designs, patients, 5-HT₃RA regimens, and definition of outcomes, and the data presented in this study, particularly regarding costs, were derived from a variety of sources, and were reported in several ways across the reviewed studies. Thus, the heterogeneity of these data prevented us from conducting a meta-analysis.

This literature review includes studies published between 1998 and 2012, many of which would not have reflected the dramatically lower cost of generic ondansetron, which became available in 2006. This may be a significant limitation in our assessment of drug costs, but it would not be expected to impact nondrug costs.

We were unable to examine the costs of managing CINV when the current prevention and treatment guidelines are being followed, because the guidelines are not organized in a way that would make it clear how to assess the costs associated with implementing various recommendations.

Future studies should develop models to compare the cost of care associated with compliant versus noncompliant treatment guideline recommendations in relation to CINV prophylaxis.

Conclusion
The use of palonosetron for CINV prophylaxis is associated with higher total acquisition costs, as well as with lower use of rescue medications and outpatient and inpatient services, compared with ondansetron or other 5-HT₃RAs in the United States. In Europe and in Canada, the total pharmacy costs and rescue medication use are lower for patients who receive palonosetron. This study supports the use of palonosetron as the preferred 5-HT₃RA, because it may lead to reduced service utilization for CINV.

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

Author Disclosure Statement
Dr Broder, Dr Sunderji, and Dr Cherepanov are employees of the Partnership for Health Analytic Research, LLC, a health services research company paid by Eisai Inc, to conduct this research; Dr Faria and Dr Powers are employees of Eisai Inc.

Dr Broder is President, Partnership for Health Analytic Research, LLC, Beverly Hills, CA; Dr Faria is Director, Health Economics and Outcomes Research, Eisai Inc, Woodcliff Lake, NJ; Dr Powers is Senior Director, Health Economics and Outcomes Research (HEOR) and Reimbursement Services, Eisai Inc, Woodcliff Lake, NJ; Dr Sunderji is Associate Medical Director, Partnership for Health Analytic Research, LLC, Beverly Hills, CA; Dr Cherepanov is Associate Director, Outcomes Research, Partnership for Health Analytic Research, LLC, Beverly Hills, CA.

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