Evaluation of an Every-other-day Palonosetron Schedule to Control Emesis in Multiple-day High-dose Chemotherapy

Aurora Mirabile; Luigi Celio; Michele Magni; Erminio Bonizzoni; Alessandro Massimo Gianni; Massimo Di Nicola

Future Oncol. 2014;10(16):2569-2578.

Abstract and Introduction

Abstract

Aim Efficacy of intermittent palonosetron dosing in patients undergoing multiple-day, high-dose chemotherapy (HDC) was investigated.

Patients & methods Fifty-eight patients received palonosetron (0.25 mg intravenous [iv.]) every other day plus daily dexamethasone (8 mg iv. twice daily) dosing. The primary end point was complete control (CC; no emesis, no rescue anti-emetics, and no more than mild nausea) in the overall acute-period (until 24 h after chemotherapy completion).

Results Acute-period CC occurred in 81% and 50% of patients receiving palonosetron and ondansetron (historical control cohort), respectively. Palonosetron (odds ratio [OR]: 4.37; p = 0.001) and a longer duration of HDC regimen (OR: 3.47; p = 0.011) independently predicted a better anti-emetic outcome.

Conclusion Palonosetron every other day plus daily dexamethasone is an effective anti-emetic coverage in patients undergoing HDC.

Introduction

Chemotherapy-induced nausea and vomiting (CINV) is still a common unwanted side-effect associated with anti-cancer chemotherapy. CINV is a contributing factor to patient morbidity and may have profound psychological implications for the patient. The intensity, onset and duration of CINV depend on the emetogenic potential and dose of anticancer agents, as well as on individual patient characteristics.^[1,2] It is well known that there is a close relationship between the risk of CINV and the use of high-dose chemotherapy (HDC) in myeloablative and non-myeloablative regimens.^[3] The emetogenic potential of HDC regimens is further increased by the multiple-day schedule of administration.^[3] The literature data indicate not only that the risk of CINV is particularly high among patients being prepared for hematopoietic stem cell transplantation (HSCT) but also that first-generation 5-HT₃ receptor antagonists (5-HT₃RA) plus dexamethasone, which is the standard anti-emetic prophylaxis in this clinical setting, achieve complete protection only in a minority of patients.^[4,5]

Palonosetron, a second-generation 5-HT₃RA, has a binding affinity for the 5-HT₃ receptor that is at least 30-fold higher than older 5-HT₃ RAs.^[6] The plasma half-life of palonosetron is approximately 40 h, markedly longer than the half-life of other antagonists, which ranges from 5 to 12 h.^[7] Two pivotal trials using single-day moderately emetogenic chemotherapy, which compared standard-dose palonosetron with a single intravenous dose of either ondansetron or dolasetron, revealed that palonosetron was associated with significantly higher rates of complete response (CR) in the acute, delayed, and overall time periods.^[8,9] A large Phase III trial assessed the efficacy of palonosetron in combination with dexamethasone compared with single-dose intravenous granisetron plus dexamethasone in patients receiving single-day highly emetogenic chemotherapy.^[10] The CR rate during the acute phase was similar in both treatment groups, while the proportion of patients with a CR was significantly higher in the palonosetron group than in the granisetron group during the delayed and overall time periods.

Taking into account the pharmacological properties of palonosetron, it is likely that, compared with first-generation antagonists, fewer doses of palonosetron may be necessary to obtain at least the same degree of protection against CINV caused by multiple-day chemotherapy regimens. Therefore, we planned the current exploratory study to assess the efficacy and tolerability of an every-other-day palonosetron schedule, in combination with daily dexamethasone dosing, for the prevention of CINV caused by common HDC regimens. Historical efficacy findings are also presented from a patient cohort, in which a similar patient population was treated at our institution with daily ondansetron plus dexamethasone in the same clinical setting.

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Table 1. Baseline patient characteristics.
Characteristic	Palo plus Dex; N (%)	Historical cohort^†; N (%)	p-value
Patients (n)	58	50
Age, years Mean ± SD (min–max) Age <40 years	45.6 ± 14.2 (20–76) 26 (44.8)	48.9 ± 11.4 (29–69) 10 (20)	0.224^‡0.006^§
Gender Female Male	18 (31) 40 (69)	18 (36) 32 (64)	0.585^§
Type of malignancy Non-Hodgkin's lymphoma Hodgkin's disease Breast cancer Testicular cancer Sarcoma	39 (67.2) 8 (13.8) 4 (7) 5 (8.6) 2 (3.4)	37 (74) 8 (16) 0 4 (8) 1 (2)	0.416^§
Alcohol consumption Never Regularly^¶	13 (22.4) 45 (77.6)	15 (30) 35 (70)	0.369^§
Chemotherapy group Cytarabine-containing^# Melphalan-containing^†† Other^‡‡	22 (37.9) 21 (36.2) 15 (25.9)	27 (54) 10 (20) 13 (26)	0.136^§
Patients receiving HSCT after chemotherapy Yes No	27 (46.5) 31 (53.5)	10 (20) 40 (80)	0.003^§

^†Historical cohort of patients receiving ondansetron plus dexamethasone.
^‡Mann-Whitney U-test (two-tailed).
^§Chi-square test (two-tailed).
^¶Moderate drinkers (one to two glasses of wine per day).
^#Regimens containing cytarabine at a dose of 4 g/m² per day.
^††Regimens containing melphalan at a single dose of 140–180 mg/m².
^‡‡High-dose regimens: etoposide + cisplatin; carboplatin; and cisplatin + etoposide + bleomycin.
Dex: Dexamethasone; HSCT: Hematopoietic stem cell transplantation; Palo: Palonosetron.

Table 2. Complete control rates for the palonosetron cohort in each time interval of acute period.
Time intervals of observation	Palo plus Dex; n/N (%)	95% CI^†	Historical cohort^‡; n/N (%)
Overall^§ (0–≤144 h)	47/58 (81.0)	68.6–90.1%	25/50 (50)
Early^¶ (0–24 h)	49/58 (84.5)	72.6–92.7%	29/50 (58)
Late^¶ (>24–≤144 h)	56/58 (96.5)	88.1–99.6%	41/50 (82)

Complete control defined as no emesis, no rescue anti-emetics, and no more than mild nausea.
^†95% confidence intervals for the palonosetron cohort.
^‡Historical cohort of patients receiving ondansetron plus dexamethasone.
^§Overall study period started with chemotherapy initiation and continued for 24 h after the last dose of chemotherapy.
^¶Early acute and late acute intervals.
Dex: Dexamethasone; n: Number of responding patients; N: Number of patients; Palo: Palonosetron.

Table 3. Anti-emetic efficacy in the overall study period for predominant group of chemotherapy, by treatment cohort.
Chemotherapy group	Complete control^†		p-value^§
Chemotherapy group	Palo plus Dex n/N (%)	Historical cohort^‡ n/N (%)	p-value^§
Cytarabine-containing^¶	21/22 (95.5)	15/27 (55.6)	0.002
Melphalan-containing^#	17/21 (81)	4/10 (40)	0.040
Other^††	9/15 (60)	6/13 (46.2)	0.705

Overall study period started with chemotherapy initiation and continued for 24 h after the last dose of chemotherapy.
^†Complete control defined as no emesis, no rescue anti-emetics, and no more than mild nausea.
^‡Historical cohort of patients receiving ondansetron plus dexamethasone.
^§Fisher's exact test (two-tailed).
^¶Regimens containing cytarabine at a dose of 4 g/m² per day.
^#Regimens containing melphalan at a single dose of 140–180 mg/m².
^††High-dose regimens: etoposide + cisplatin; carboplatin; and cisplatin + etoposide + bleomycin.
Dex: Dexamethasone; n: Number of responding patients; N: Number of patients; Palo: Palonosetron.

Table 4. Adjusted odds ratios of achieving complete control in the overall study period among 108 patients.
Variable (comparison)	Odds ratio^†	95% CI	p-value
Anti-emetic prophylaxis (palonosetron vs ondansetron regimen)^‡	4.37	(1.82–11.16)	0.001
Age (<50 vs ≥50 years)	1.50	(0.59–3.94)	0.396
Gender (female vs male)	0.62	(0.12–3.61)	0.564
Alcohol consumption (never vs regularly)^§	0.96	(0.15–5.54)	0.960
Chemotherapy duration (6 vs ≤5 days)	3.47	(1.36–9.56)	0.011

Complete control defined as no emesis, no rescue anti-emetics, and no more than mild nausea. Overall study period started with chemotherapy initiation and continued for 24 h after the last dose of chemotherapy.
^†Odds ratio bigger than 1 indicates an increased likelihood of achieving complete control.
^‡Patients received palonosetron or ondansetron, both given with daily dexamethasone dosing.
^§One to two glasses of wine per day.

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Evaluation of an Every-other-day Palonosetron Schedule to Control Emesis in Multiple-day High-dose Chemotherapy

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