Granisetron Extended-Release Subcutaneous Injection versus Palonosetron Infusion for CINV Prevention: Cost Comparison of Unscheduled Hydration

Abstract

Background

Granisetron extended-release subcutaneous (SC) injection is a novel formulation of granisetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Palonosetron is administered intravenously and is indicated for CINV prevention in acute and delayed phases after the use of moderately emetogenic chemotherapy (MEC) and in the acute phase after highly emetogenic chemotherapy (HEC). No data are available regarding the impact of SC granisetron on the cost of unscheduled hydration compared with other antiemetic drugs, specifically the older-generation palonosetron.

Objective

To compare the costs of unscheduled hydration associated with breakthrough CINV after SC granisetron versus palonosetron administration in patients receiving MEC or HEC.

Methods

This retrospective analysis was based on electronic medical records data from a single multicenter, community-based practice involving patients receiving MEC or HEC with a 3-drug antiemetic regimen, including a neurokinin-1 receptor antagonist, dexamethasone, and either SC granisetron or palonosetron. A cost-of-care analysis for SC granisetron and palonosetron was based on the maximum per-unit Medicare reimbursement amounts for the use of unscheduled hydration, administration of rescue antiemetic drugs, laboratory tests, and patient office evaluations.

Results

A total of 182 patient records were evaluated, 91 for patients receiving SC granisetron and 91 receiving palonosetron. The mean per-patient cost of care related to unscheduled hydration in patients receiving HEC or MEC was significantly lower with SC granisetron ($296) than palonosetron ($837; P <.0001), including subset analysis of patients requiring additional care (SC granisetron [$691], N = 39; palonosetron [$1058], N = 72; P = .0260). The mean hydration costs per patient receiving HEC or MEC were lower with SC granisetron ($62) than with palonosetron ($253; P <.0001). The hydration costs per patient receiving only HEC were lower with SC granisetron ($66) than palonosetron ($280; P <.0001). The per-patient costs were lower when SC granisetron was administered than when palonosetron was administered as part of the antiemetic regimen, except for the cost of rescue antiemetic drug in patients receiving MEC. Fewer median unscheduled hydration therapies per patient were used with SC granisetron versus palonosetron (HEC, 3 vs 5; MEC, 2 vs 3).

Conclusion

The use of SC granisetron reduced the total per-patient costs of care associated with unscheduled hydration compared with palonosetron in patients receiving HEC or MEC for breakthrough CINV events.

New antiemetic agents and multidrug regimens are available for the prophylactic treatment of chemotherapy-induced nausea and vomiting (CINV) and comprehensive antiemetic guidelines are available.1–4 Nevertheless, breakthrough CINV is a common clinical problem, affecting up to 40% of patients with cancer who are receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC).5 Dehydration and the resultant need for hydration therapy is a consequence of breakthrough CINV. The costs associated with breakthrough CINV can be substantial, including those associated with unscheduled hydrations.6

KEY POINTS

• ▸Breakthrough CINV is a common clinical problem, affecting up to 40% of patients with cancer who receive a MEC or a HEC regimen.
• ▸This study compared the cost of unscheduled hydration in patients receiving HEC or MEC with SC granisetron or palonosetron as part of a 3-drug antiemetic regimen.
• ▸The mean per-patient cost for unscheduled hydration in patients receiving HEC or MEC was significantly lower with SC granisetron than palonosetron (P <.0001).
• ▸The hydration costs per patient receiving HEC were lower with SC granisetron ($66) than palonosetron ($280; P <.0001).
• ▸Lower per-patient costs were seen with SC granisetron than with palonosetron, with the exception of rescue antiemetic drug costs in patients receiving MEC.
• ▸Fewer median unscheduled hydration therapies per patient were used with SC granisetron versus palonosetron.
• ▸Using SC granisetron rather than palonosetron as part of a 3-drug antiemetic regimen may reduce the need for unscheduled hydration after HEC or MEC therapy.

Granisetron extended-release (ER) subcutaneous (SC) injection is a novel formulation of first-generation granisetron that provides a therapeutic effect for 5 days after a single SC dose to prevent acute and delayed CINV.7 SC granisetron ER is administered as part of a guideline-recommended antiemetic regimen before chemotherapy.8,9 Palonosetron is a 5-hydroxytryptamine type 3 (5-HT₃) receptor antagonist with a t_1/2 of approximately 40 hours.10

Phase 3 clinical trials of combination antiemetic regimens have demonstrated the noninferiority of SC granisetron ER to palonosetron in the prevention of acute CINV associated with a MEC or a HEC regimen and in the prevention of MEC- and HEC-associated delayed CINV.11,12 In the Modified Absorption of Granisetron in the Prevention of CINV clinical trial—and as part of a 3-drug antiemetic regimen, including 5-HT₃ receptor antagonist, fosaprepitant, and dexamethasone—SC granisetron was superior to ondansetron in the prevention of emesis or the need for rescue medication in HEC-associated delayed CINV.13

Palonosetron was approved in 2003 for the prevention of acute and delayed nausea and vomiting associated with MEC and the prevention of acute nausea and vomiting associated with HEC.14 SC granisetron ER was approved in 2016 for the prevention of acute or delayed CINV in patients receiving MEC or anthracycline and cyclophosphamide (ie, HEC) combination chemotherapy regimens.15 The National Comprehensive Cancer Network (NCCN) guidelines list SC granisetron and palonosetron as preferred 5-HT₃ receptor antagonists, in combination with dexamethasone, for the prevention of MEC-associated CINV, and is a Category 1 recommendation, when combined with olanzapine, dexamethasone, and a neurokinin-1 receptor antagonist, for the prevention of HEC-associated CINV.1

CINV negatively affects patients' overall health status, quality of life, and the ability to adhere to their prescribed course of chemotherapy.16–22 In addition, the impact of CINV extends to resource utilization and healthcare costs,21,23–25 which are affected by the associated need for rescue medication, hydration, correction of electrolyte imbalances, and hospitalization.1,5

Previously, our group performed a retrospective analysis to evaluate the requirement for CINV-related hydration among patients receiving SC granisetron or palonosetron for the prevention of MEC- or HEC-associated CINV in a community practice.26 Our study showed a significant benefit with SC granisetron versus palonosetron in reducing hydration requirements (mean hydration event, 0.3 vs 0.9, respectively; standard deviation, 0.6 vs 1.1, respectively; P <.0001).26 In addition, 78% of patients who received palonosetron required additional hydration 24 hours or more postchemotherapy through day 6 compared with 42% of patients who received SC granisetron.26

Based on the findings from the previous study, the goal of this current study was to analyze the impact of using SC granisetron versus palonosetron on the cost of unscheduled hydration associated with breakthrough CINV in patients receiving HEC or MEC.

Methods

This was a retrospective analysis of a multisite (24 locations) community-based practice, for which detailed methodology has been previously described.26 Briefly, consecutive patients with cancer were identified for data extraction from the electronic medical record system. These patients were scheduled to receive MEC or HEC and a recommended 3-drug antiemetic regimen—including a neurokinin-1 receptor antagonist, dexamethasone, and a 5-HT₃ receptor antagonist—based on the NCCN antiemesis guidelines at the time of the clinic visit.27

The specific 5-HT₃ receptor antagonists used included SC granisetron only, palonosetron only, or palonosetron that was switched to SC granisetron. In all cases, the dosing was 10 mg subcutaneously for SC granisetron ER and 0.25 mg intravenously for palonosetron, each administered with fosaprepitant 150 mg intravenously and dexamethasone 10 mg.26

As previously reported, hydration use (ie, the number of unscheduled hydration therapies per chemotherapy cycle) was compared between patients receiving SC granisetron only (N = 91) between October 2016 and June 2017; palonosetron only (N = 93) between January 2016 and June 2017; and patients who switched from palonosetron to SC granisetron between May 2016 and May 2017, because of a practice decision to use SC granisetron as the preferred 5-HT₃ receptor antagonist for MEC and HEC regimens (N = 48).26

In performing the current cost analysis, we determined that 2 patients in the palonosetron-only group had been switched to SC granisetron, resulting in 91 patients who received palonosetron only being included in this current analysis. In the current cost analysis, we focused only on the patients receiving SC granisetron (N = 91) or palonosetron (N = 91), and did not include the patients who switched from palonosetron to SC granisetron (Table 1).

Table 1.

Patient Demographics and Baseline Characteristics

Patient characteristics	SC granisetron ER cohort (N = 91)	Palonosetron cohort (N = 91)	Total (N = 182)
Age, mean (min, max), yrs	63 (32, 87)	66 (39, 90)	65 (32, 90)
Sex
Men, N (%)	26 (29)	28 (31)	54 (30)
Women, N (%)	65 (71)	63 (69)	128 (70)
Cancer type
Breast, N (%)	18 (20)	19 (21)	37 (20)
Bronchus or lung, N (%)	22 (24)	28 (31)	50 (27)
Gastrointestinal, N (%)	21 (23)	9 (10)	30 (17)
Genitourinary, N (%)	2 (2)	3 (3)	5 (3)
Gynecologic, N (%)	10 (11)	16 (18)	26 (14)
Leukemia/lymphoma, N (%)	15 (17)	11 (12)	26 (14)
Other, N (%)	3 (3)	5 (5)	8 (4)
Emetogenicity (per NCCN guidelines)a
HEC, N (%)	55 (60)	76 (84)	131 (72)
MEC, N (%)	36 (40)	15 (16)	51 (28)
Radiation therapy
Yes, N (%)	12 (13)	22 (24)	34 (19)

^aEmetogenicity was based on the NCCN antiemesis guidelines.1

ER indicates extended-release; HEC, highly emetogenic chemotherapy; max, maximum; MEC, moderately emetogenic chemotherapy; min, minimum; NCCN, National Comprehensive Cancer Network; SC, subcutaneous.

In evaluating the costs of care associated with unscheduled hydration, the components of care assessed (chemotherapy cycles 1–4; days 2–6 postchemotherapy), and the Current Procedural Terminology (CPT) codes for each component of care are summarized in Table 2.

Table 2.

Components of Care and CPT Code Description

CPT code	Description
Unscheduled hydration
96360	IV infusion hydration initial 31 min-1 hour
96361	IV infusion hydration each additional hour
Rescue antiemetic administration
96365	IV infusion up to 1 hour
96367	IV infusion first hour of additional sequential drug
96372	IM/SC injection
96374	IV push initial
96375	IV push additional/different drug each
Rescue antiemetic drugs
Antiemetic
J1616	Granisetron 100 mcg
J2469	Palonosetron 25 mcg
Fluids
J3480	Potassium chloride per 2 mEq
J7030	Saline 1000 mL
J7040	Saline 500 mL
J7050	Saline 250 mL
Laboratory
36415	Venipuncture
80048	Basic metabolic panel total calcium
80053	Comprehensive panel
85025	Blood count w/differential WBC count
85027	CBC/platelet
Office evaluations
99213	Office visit expanded
99214	Office visit detailed
99215	Office visit comprehensive
99245	Office consult high

CBC indicates complete blood count; CPT, Current Procedural Terminology; IM, intramuscular; IV, intravenous; SC, subcutaneous; WBC, white blood cell.

We calculated the costs for each of these components, which were all based on the maximum per-unit Medicare reimbursement amounts (adjusted based on reimbursement rates from January 2016 through June 2017), and were subsequently totaled. We also performed an analysis by the type of chemotherapy received (ie, MEC or HEC).

The per-patient cost analysis for each component of care was calculated by the drug each patient received (ie, SC granisetron or palonosetron), as well as by whether the patients required additional components of care as a direct result of an unscheduled hydration visit, including hydration, rescue antiemetic drugs (SC granisetron or palonosetron), or fluids (potassium chloride per 2 mEq/mL saline 1000 mL, saline 500 mL, saline 250 mL), and drug administration, laboratory tests, and patient office evaluations.

All comparisons reported here were for the SC granisetron and palonosetron groups, excluding those who switched from palonosetron to SC granisetron. Nonparametric 2-sided Wilcoxon rank-sum tests were used to test the null hypothesis of no difference between the 2 groups in the costs of care.

Results

A total of 182 patients were included in the study, 91 patients who received SC granisetron between October 2016 and June 2017, and 91 patients who received palonosetron between January 2016 and June 2017. Baseline demographic and clinical characteristics are summarized in Table 1. The study population was predominantly female (N = 128; 70%), with bronchus or lung cancer (N = 50; 27%) as the most common diagnosis.

In the group that received SC granisetron, 55 patients had received HEC and 36 patients had received MEC. In the group that received palonosetron, 76 patients had received HEC and 15 patients had received MEC. To account for the imbalances in the number of patients who received HEC and MEC between the 2 groups, a per-patient analysis was conducted.

All components of care related to unscheduled hydration clinic visits and their respective CPT codes used for the analysis are summarized in Table 2. The incurred per-patient costs for all components of care related to an unscheduled hydration visit in patients receiving HEC or MEC were significantly lower in the group that received SC granisetron than in the group that received palonosetron (mean, $296 vs $837, respectively; P <.0001; median, $0 vs $587, respectively; Table 3 and Appendix Figure 1, available at www.AHDBonline.com).

Table 3.

Per-Patient Reimbursement Costs, by Care Component at Time of Unscheduled Hydration

Cost component	Per-patient reimbursement costsa			Per-patient reimbursement costs (patients requiring additional care)
	SC granisetron ER cohort, $ (N = 91)	Palonosetron cohort, $ (N = 91)	P valueb	SC granisetron ER cohort, $ (N = 39)	Palonosetron cohort, $ (N = 72)	P valueb
Unscheduled hydration	62	253	<.0001	146	320	.0114
Rescue antiemetic administration	49	140	<.0001	115	177	.0227
Rescue antiemetic drugs	61	115	<.0001	142	146	.0953
Laboratory	16	50	<.0001	38	63	.0647
Office evaluation	108	279	.0002	251	352	.5942
Total	296c	837d	<.0001	692	1058	.0260

^aValues represent the mean.

^bP values are from Wilcoxon rank-sum test.

^cThe median value for SC granisetron was $0.

^dThe median value for palonosetron was $587.

ER indicates extended-release; SC, subcutaneous.

The difference in the subset of patients who required additional hydration-related care (N = 39 for SC granisetron, N = 72 for palonosetron; Table 3) remained significant, because the cost for all components of care was lower for patients who received SC granisetron than for patients who received palonosetron ($692 vs $1058, respectively; P = .0260).

For the HEC group, those who received SC granisetron (N = 55) had a significantly lower per-patient cost associated with all components of care for unscheduled hydrations compared with patients who received palonosetron (N = 76; mean $343 vs $933, respectively; P <.0001; median, $0 vs $680, respectively; Table 4 and Appendix Figure 2A, available at www.AHDBonline.com).

Table 4.

Reimbursement Costs, by HEC or MEC at Time of Clinic Visit for Unscheduled Hydration

Cost component	Per-patient reimbursement costsa						Per-patient reimbursement costs (patients requiring additional costs)a
	SC granisetron ER cohort, $ (N = 55)	Palonosetron cohort, $ (N = 76)	P valueb	SC granisetron ER cohort, $ (N = 36)	Palonosetron cohort, $ (N = 15)	P valueb	SC granisetron ER cohort, $ (N = 23)	Palonosetron cohort, $ (N = 62)	P valueb	SC granisetron ER cohort, $ (N = 16)	Palonosetron cohort, $ (N = 10)	P valueb
Unscheduled hydration	66	280	<.0001	57	115	.1079	158c	344	.0425	128	173	.4908
Rescue antiemetic administration	63	155	<.0001	28	66	.0986	151	190	.1674	63	99	.6083
Rescue antiemetic drugs	79	137	<.0001	32	3	.1939	190	168	.3373	73	4	1.0000
Laboratory	18	55	<.0001	13	21	.1900	44	68	.1691	29	32	.8946
Office evaluation	117	306	.0007	93	143	.5675	280	374	.6478	208	215	.4742
Total	343	933	<.0001	223	348	.2219	823	1144	.1240	501	523	.8536

^aValues represent the mean.

^bP values are from Wilcoxon rank-sum test.

^cN = 22; 1 patient did not receive hydration but received other components of care.

ER indicates extended-release; HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy; SC, subcutaneous.

The same analysis of patients who received MEC resulted in lower per-patient costs in the 36 patients who received SC granisetron than in the 15 patients who received palonosetron (mean, $223 vs $348, respectively; P = .2219; median, $0 vs $182, respectively; Table 4 and Appendix Figure 2B, available at www.AHDBonline.com).

Similar findings were observed in patients who required additional hydration-related care in the SC granisetron and palonosetron groups for HEC (N = 23; $823 vs N = 62; $1144, respectively) and for MEC (N = 16; $501 vs N = 10; $523, respectively).

In a further analysis of the costs for patients who required additional care at an unscheduled hydration, those who received HEC and SC granisetron had lower costs than patients who received HEC and palonosetron (maximum, $2504 vs $6595; median, $525 vs $856; mean, $823 vs $1144, respectively; Table 5).

Table 5.

Costs for All Components of Care, by HEC and MEC, of Patients Requiring Additional Care at Time of Unscheduled Hydration

Drug regimen		Patients, N	Costs
			Minimum, $	Maximum, $	Median, $	Mean, $	Mean (total patients), % (N)
SC granisetron ER only	HEC	23	82	2504	525	823	344 (55)
	MEC	16	158	1339	317	500	223 (36)
Palonosetron only	HEC	62	89	6595	856	1144	933 (76)
	MEC	10	130	1282	273	522	348 (15)

ER indicates extended-release; HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy; SC, subcutaneous.

A summary of the number of unscheduled hydrations and associated clinic visit costs, which were calculated using CPT codes 96360 and 96361, is shown in Table 6. For the HEC group, the number of unscheduled hydrations were lower in the SC granisetron group than in the palonosetron group (maximum, 16 vs 73, respectively; median, 3 vs 5, respectively; mean, 4 vs 8, respectively).

Table 6.

Summary of Unscheduled Hydrations and Costs^a

Drug regimen		Patients requiring unscheduled hydrations, N	Unscheduled hydrations						Unscheduled hydration costs
			Total patients, N	Minimum, N	Maximum, N	Median, N	Mean, N	Mean (total patients), N	Minimum, $	Maximum, $	Median, $	Mean, $	Mean cost (total patients), $ (N)
SC granisetron ER only	HEC	22	93	1	16	3	4	2 (55)	18	452	125	166	66 (55)
	MEC	16	43	1	10	2	3	1 (36)	18	393	89	128	57 (36)
Palonosetron only	HEC	62	500	1	73	5	8	7 (76)	18	3297	228	344	280 (76)
	MEC	10	38	1	8	3	4	3 (15)	18	404	125	173	115 (15)

^aIncludes only Current Procedural Terminology codes 96360 and 96361.

ER indicates extended-release; HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy; SC, subcutaneous.

Similarly, the associated costs of unscheduled hydration when using CPT codes 96360 and 96361 were lower in the SC granisetron group (N = 22) than in the palonosetron group (N = 62; maximum, $452 vs $3297, respectively; median, $125 vs $228, respectively; mean, $166 vs $344, respectively). In addition, the costs for the patients who received MEC followed by SC granisetron were lower than for patients who received MEC followed by palonosetron; however, these differences were not significant (Table 6).

Discussion

In this retrospective cost analysis of patients who received HEC or MEC at a community-based multisite clinic, the per-patient cost of care associated with unscheduled hydrations was lower for patients who received SC granisetron than for patients who received palonosetron. All components of the per-patient costs were lower among SC granisetron recipients than palonosetron recipients, with a particularly notable difference in the costs for unscheduled hydration between the 2 groups.

Furthermore, lower costs were incurred in patients who received SC granisetron compared with those who received palonosetron as part of a HEC regimen. In the subgroup of patients requiring additional care, lower costs and a lower total number of unscheduled hydrations were incurred after SC granisetron treatment compared with palonosetron treatment.

Palonosetron confers clinical and economic benefits over 5-HT₃ receptor antagonists (including ondansetron, dolasetron, and granisetron).28,29 However, there are some conflicting data and remaining questions regarding its advantages over older agents.9 Given the results of our previously published primary analysis, in which the use of SC granisetron resulted in 3 times fewer CINV-related hydration events than palonosetron per chemotherapy cycle,26 a corresponding reduction in unscheduled hydration-related costs was expected.

In this current analysis, we also identified savings in other components of care that are a direct result of unscheduled hydration visits, including the costs for rescue antiemetic drugs and their administration, laboratory tests, and patient office evaluation.

Of note, in another retrospective study of hydration use in patients receiving SC granisetron or palonosetron in conjunction with MEC or HEC regimens, significant benefits were seen for SC granisetron versus palonosetron with respect to the mean scheduled hydration rate per treatment cycle (0.2 vs 0.6, respectively; P = .0005), as well as the proportion of patients requiring any hydration (33% vs 54%, respectively; P = .0033),30 which aligns with our primary findings.26

Overall, the results of the current cost analysis pertaining to unscheduled hydrations are consistent with, and expand on, previous observations regarding the propensity of inadequately controlled (ie, breakthrough) CINV to increase healthcare resource utilization and the associated costs, including those related to outpatient, inpatient, and emergency department care.21,23–25,31 Unscheduled hydration may be an additional suitable surrogate event for measuring breakthrough CINV that aligns with cost-effective cancer care.6

The results of a prespecified analysis of the De-ESCALaTE trial, which demonstrated superiority of cisplatin versus cetuximab with radiotherapy for head and neck cancer, lend further support to the importance of adequate hydration and antiemetic prophylaxis for HEC (cisplatin)-related CINV and dehydration.32 In that analysis, for which results have been presented but not yet published as of this writing, the use of triple antiemetic regimens postchemotherapy, intravenous fluids pre- and postchemotherapy, and oral fluids were all significant predictors of serious adverse events.32

New studies that further investigate 5-HT₃ receptor antagonists and the association between complete response and unscheduled hydrations in patients receiving HEC or MEC regimens can be valuable to help achieve the optimal control of CINV.

Limitations

We acknowledge that this analysis has several limitations, including those related to retrospective analyses based on data extraction from electronic medical records in real-world practice. Although the data were derived from 24 practice sites, they were all part of the same practice, which limits their generalizability.

Furthermore, the costs analyzed in this study are specific to the costs incurred in the outpatient setting (ie, hydration) and do not capture the costs of all the components of care of the emergency department or inpatient services.

In addition, the cost difference between SC granisetron and palonosetron for CINV prophylaxis was not included in this analysis, which focused on the costs of components of care (ie, rescue antiemetic drug administration, laboratory tests, and patient office evaluations) related to unscheduled hydration that resulted from breakthrough CINV.

Conclusion

The results of this analysis indicate that the use of SC granisetron versus palonosetron as a component of a 3-drug antiemetic regimen can reduce the need for unscheduled hydration in patients receiving HEC or MEC for breakthrough CINV. Similarly, it can reduce the need for additional concomitant care elements (ie, rescue antiemetic administration/drugs, laboratory tests, patient office evaluations), which can result in an overall lower per-patient cost of care related to unscheduled hydration in this patient population.