Palonosetron in pediatric patients: A single-center,retrospective evaluation of policy and clinical practice guideline discordance

Abstract

Introduction

Clinical practice guidelines (CPGs) recommending palonosetron for the prevention and management of chemotherapy-induced nausea and vomiting (CINV) were adapted for use at our institution. Palonosetron was restricted for use in patients experiencing breakthrough CINV and receiving highly emetogenic chemotherapy (HEC) or undergoing stem cell transplant conditioning and in patients with refractory CINV receiving HEC. Given the significant cost of palonosetron, we aimed to determine the proportion of chemotherapy blocks where palonosetron use was discordant with the institutional policy or source CPG.

Methods

A retrospective review of the health records of patients who received palonosetron between 1 July 2019 and 30 June 2020 was undertaken. Details of palonosetron use, antiemetic regimen and the date and time of each vomit during the acute and delayed phases were collected for each chemotherapy block where palonosetron was given. Discordance with the institutional policy and the source CPG was determined by assessing the indication for palonosetron and the dose. In the subset of chemotherapy blocks where information regarding vomiting episodes was available, the extent of acute phase chemotherapy-induced vomiting (CIV) control was reported.

Results

Four hundred thirty-eight chemotherapy blocks, representing 122 patients (mean age 9 years), receiving 595 palonosetron doses were included. Palonosetron use was discordant with institutional policy during most (72%; 314/438) of the chemotherapy blocks analyzed. However, palonosetron use was concordant with the source CPG during most chemotherapy blocks (74%; 326/438). Complete CIV control during the acute phase was observed in 66% (195/295) of chemotherapy blocks where palonosetron was given, irrespective of concomitant antiemetics administered.

Conclusion

The majority of palonosetron use at our institution was discordant with institutional policy, but concordant with the source CPG. Our institutional policy has since been updated to be more aligned with the source CPG.

Keywords

Palonosetron chemotherapy nausea and vomiting

Introduction

Chemotherapy-induced nausea and vomiting (CINV) are problematic treatment-related adverse effects.¹ However, the use of clinical practice guideline (CPG)-consistent CINV prophylaxis has led to substantial improvements in CINV control.^2–5 Current pediatric CPGs for prophylaxis of acute CINV in chemotherapy-naïve patients or those who have not experienced breakthrough or refractory chemotherapy-induced vomiting (CIV) (primary prophylaxis) recommend a serotonin receptor antagonist (5-HT3RA; e.g. ondansetron, granisetron or palonosetron) alone or in combination with other antiemetic agents.^6–10 Palonosetron differs from ondansetron and granisetron in that it induces receptor internalization prolonging the inhibition of receptor function.¹⁰ Compared to other 5-HT3RAs, palonosetron alone or in combination with dexamethasone may result in improved CINV control in patients receiving highly emetogenic chemotherapy (HEC).^9,11,12 Further, palonosetron use during the acute phase is superior to ondansetron and granisetron in controlling vomiting during the delayed phase.^9,12 5-HT3RAs do not appear to differ significantly in terms of safety.¹³

SickKids’ CINV prevention and management policy was updated in 2017 using the most recent CPG at that time.⁶ Due to the high cost of palonosetron, the SickKids’ policy limited its use to breakthrough CINV management in patients receiving HEC or hematopoietic stem cell transplant/cellular therapy (HSCT/CT) conditioning containing HEC or prophylaxis in patients with refractory CINV about to receive HEC (secondary prophylaxis).¹⁴ The SickKids’ policy also included palonosetron dosing recommendations. Patients 12 years of age and older could receive either palonosetron orally or intravenously (IV). The palonosetron IV dose was capped at 1.5 mg for patients 17 years of age and older. CPG recommendations and the adapted SickKids’ policy statements are summarized in Supplemental Table S1.

This study was undertaken to determine the level of discordance between actual palonosetron use and our institutional CINV policy and the CPG from which the policy was adapted.

Methods

A retrospective review was conducted from 1 July 2019 to 30 June 2020 at SickKids, an academic, pediatric hospital in Toronto, Canada. The primary objective was to determine the discordance of palonosetron use with (a) the SickKids’ policy for CINV prevention and treatment (policy-discordant) and (b) the CPGs upon which our policy was based (CPG-discordant). The secondary objectives were to describe (a) characteristics of policy-discordant and CPG-discordant palonosetron use and (b) the extent of acute phase CIV control experienced by patients receiving palonosetron.

Patients

All oncology and HSCT/CT patients less than 18 years old who received at least one IV or oral palonosetron dose at SickKids during an inpatient admission or an ambulatory clinic visit during the indicated timeframe were included. Eligible patients were identified through a drug utilization report from the electronic health record. Patients who received palonosetron but were not under the care of the oncology service or were not undergoing HSCT/CT were excluded.

Data collected

Data collected from the health record were demographic information, chemotherapy regimen, CIV control history, details of palonosetron use, antiemetic regimen and the date and time of each vomit during the acute and delayed phases. Data were collected for each chemotherapy block (period of consecutive days of IV and/or intramuscular chemotherapy administration) that included palonosetron, starting at the beginning of the acute phase and continuing until the end of the delayed phase. The acute phase started with administration of the first chemotherapy dose of the chemotherapy block and ended 24 h following the last chemotherapy dose in the chemotherapy block.^14,15 The delayed phase started at the end of the acute phase and continued for 96 h.^14,15 Chemotherapy regimen emetogenicity was assigned using the pediatric chemotherapy emetogenicity classification CPG.¹⁶ If the chemotherapy was not listed in this CPG, the American Society of Clinical Oncology, Multinational Association of Supportive Care in Cancer or National Comprehensive Cancer Network classifications were used sequentially as necessary.^17–19

Analysis

Descriptive statistics were utilized to describe the characteristics of patients receiving palonosetron and reasons for its use.

Discordance with the institutional policy and the source CPG was determined by assessing whether the palonosetron indication and dose matched those indicated in Supplemental Table S1. Doses were considered policy- or CPG-discordant if they differed from the recommended doses by more than 10%. Policy- and CPG-discordant chemotherapy blocks were not mutually exclusive.

CIV control was reported as a proportion in the subset of chemotherapy blocks where palonosetron was given for CIV prophylaxis and for which information regarding vomiting episodes were available in the health record. Complete CIV control was defined as no emesis and no rescue medication use during the phase of interest.¹⁶ Partial and failed CIV control were defined as 1–2 or 3 or more emetic episodes in 24 h during the phase of interest, respectively.¹⁷

Results

One hundred thirty-six patients were screened for study inclusion based on a computer-generated report, 14 patients excluded, reasons for exclusion were no chemotherapy administered, no palonosetron administered, palonosetron dose administered outside the study period, concurrent total body irradiation and patient greater than 18 years (Figure S1).

Four hundred and thirty-eight chemotherapy blocks, representing 122 patients, receiving 595 palonosetron doses were included. Each patient contributed a median of 2 (range: 1 to 45) chemotherapy blocks. Characteristics of patients, chemotherapy blocks and palonosetron use are summarized in Table 1.

Table 1.

Characteristics of included patients, chemotherapy blocks during which palonosetron was administered and palonosetron dosing.

	All^a	Policy- discordant	CPG- discordant
PATIENT CHARACTERISTICS^b	N = 122	N = 90	N = 29
Mean age in years (range)	9 (0–18)	9 (0–17)	12 (1–17)
Number of male patients (%)	72 (59)	54 (60)	17 (59)
Chemotherapy indication, number of chemotherapy blocks (%)	N = 438	N = 314	N = 112
Leukemia and lymphoma	159 (36)	101 (32)	28 (25)
Solid tumor	213 (49)	171 (54)	80 (71)
HSCT/CT	66 (15)	42 (13)	4 (4)
CHEMOTHERAPY BLOCK CHARACTERISTICS	N = 438	N = 314	N = 112
Emetogenicity, number of chemotherapy blocks (%)
HEC	284 (65)	167 (53)	40 (36)
MEC	75 (17)	69 (22)	15 (13)
LEC	45 (10)	44 (14)	31 (28)
MinEC	34 (8)	34 (11)	26 (23)
Duration, number of chemotherapy blocks (%)
1-day	204 (47)	111 (35)	46 (41)
2-day	68 (16)	117 (37)	46 (41)
3-day	58 (13)	31 (10)	3 (3)
4-day	24 (5)	18 (6)	6 (5)
5-day	84 (19)	37 (12)	11 (10)
Concurrent CINV prophylaxis, number of chemotherapy blocks (%)
Palonosetron alone	195 (45)	152 (48)	71 (63)
Palonosetron and dexamethasone	33 (8)	23 (7)	7 (6)
Palonosetron and nabilone	119 (27)	76 (24)	13 (12)
Palonosetron and olanzapine	9 (2)	4 (1)	3 (3)
Palonosetron, dexamethasone and aprepitant	59 (13)	44 (14)	13 (12)
Palonosetron, dexamethasone and metoclopramide	2 (0.5)	2 (0.6)	0 (0)
Palonosetron, dexamethasone and nabilone	20 (5)	12 (4)	5 (4)
Palonosetron, dexamethasone and olanzapine	1 (0.2)	1 (0.3)	0 (0)
PALONOSETRON DOSE CHARACTERISTICS	N = 595	N = 428 (72)	N = 159 (27)
Route of administration, number of doses (%)
IV	520 (87)	353 (82)	90 (57)
PO	75 (13)	75 (18)	69 (43)
Median number of doses/patient (IQR)
IV	4 (2–7)	3 (2–5.5)	3(2–8)
PO	2 (1–13.5)	2 (1–35.5)	1(1–13.5)
Indication for palonosetron use, number of chemotherapy blocks (%)	N = 438	N = 314	N = 112
Primary prophylaxis	190 (43)	190 (61)	49 (44)
Breakthrough CINV	32 (7)	15 (5)	4 (4)
Refractory CINV	216 (49)	109 (35)	59 (53)

CPG, clinical practice guideline; HSCT/CT, Hematopoietic stem cell transplant/cellular therapy; HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy; LEC, low emetogenic chemotherapy; MinEC, minimally emetogenic chemotherapy; CINV, chemotherapy-induced nausea and vomiting; IV, intravenously.

^aAll chemotherapy blocks analyzed.

^bReported at the first included chemotherapy block within the study period.

Table 2.

Reasons for discordant palonosetron use by number of chemotherapy blocks.

Reasons for discordant palonosetron use^a	Policy-discordant, N (%), N = 314	CPG-discordant, N (%), N = 112
Primary prophylaxis	178 (57)	0 (0)
Discordant emetogenicity	81 (26)	22 (20)
Discordant dose (dose too low)
Intravenous	14 (4)	51 (46)
Oral	4 (1)	31 (28)
Discordant dose and discordant emetogenicity	25 (8)	8 (7)
Discordant dose and primary prophylaxis	12 (4)	0 (0)

CPG, clinical practice guideline.

^aNote that palonosetron use was policy-concordant or CPG-concordant during 124 and 326 chemotherapy blocks, respectively.

Palonosetron use was policy-discordant or CPG-discordant during 314 (72%) and 112 (26%) chemotherapy blocks, respectively (Table 2). The most common reason for policy-discordance was the use of palonosetron for primary CINV prophylaxis (57%; 178/314; see Table S1 for definitions). The most common reason for CPG discordance was prescription of a lower-than-recommended palonosetron dose (73%; 82/112).

Acute phase CIV control was evaluated in 295 chemotherapy blocks; data were insufficient to evaluate delayed phase CIV control. Complete CIV control during the acute phase was achieved in 66% (195/295) of chemotherapy blocks when palonosetron was administered for primary prophylaxis, refractory or breakthrough CIV, regardless of chemotherapy emetogenicity and concurrent antiemetics received. The antiemetic regimens prescribed and reported CIV control are summarized in Supplemental Table S2.

Discussion

During the study period, palonosetron use at our institution was largely discordant with institutional policy but concordant with the CPG recommendations.

The benefits of CPG-consistent care are well established. CPG-consistent care has improved patient outcomes in CINV prevention.^2,3,20–22 Yet, in practice, the extent of CPG implementation tends to be low.²⁰ Variation in CPG uptake may be explained by organizational factors including prioritization of evidence-based care and the availability of resources to implement CPGs.²⁰ Institutions may balance these factors differently than clinicians and patients.

It is interesting that CPG-discordant palonosetron use was lower than policy-discordant use in our study. Adaptation of the 2017 CPG to create the SickKids’ policy incorporated an effort to contain palonosetron costs by restricting its use. It is to be expected that institutional resources would be heavily weighted in the adaptation of the source CPG recommendations. We speculate that many clinicians involved in antiemetic selection for patients were aware of the source CPG and the evidence underpinning its recommendations and applied this knowledge when making patient-specific decisions. After study completion, the SickKids’ policy was updated in 2022 to include palonosetron for primary prophylaxis in patients receiving HEC who are not able to receive dexamethasone and aprepitant.²³ This reflects the actual palonosetron use seen during our study period and aligns with the updated CINV CPG which strongly recommends the use of palonosetron over other 5HT3RAs for patients receiving HEC for whom either dexamethasone, fos(aprepitant) or both are not suitable.⁹

Our study was limited due to its retrospective nature. Its strength was the consistent application of data element definitions.

Despite policy limitations on palonosetron use, it was commonly used for primary prophylaxis at our institution during the study period. With a recent policy update, future palonosetron use will likely align with both healthcare professional values and current CPG recommendations.

Supplemental Material

sj-docx-1-opp-10.1177_10781552241233489 - Supplemental material for Palonosetron in pediatric patients: A single-center, retrospective evaluation of policy and clinical practice guideline discordance

Supplemental material, sj-docx-1-opp-10.1177_10781552241233489 for Palonosetron in pediatric patients: A single-center, retrospective evaluation of policy and clinical practice guideline discordance by Meredith Ames, Priya Patel, L Lee Dupuis and Alicia Koo in Journal of Oncology Pharmacy Practice

Footnotes

Author statement

LD and AK conceived the study. MA and PP researched the literature. All authors were involved in protocol development. MA was involved in data analysis. MA wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

Data availability

Raw data were generated at The Hospital for Sick Children. Derived data supporting the findings of this study are available from the corresponding author MA on request.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Meredith Ames

L Lee Dupuis

Supplemental material

Supplemental material for this article is available online.

References

Sepúlveda-Vildósola

Betanzos-Cabrera

Lastiri

, et al. Palonosetron hydrochloride is an effective and safe option to prevent chemotherapy-induced nausea and vomiting in children. Arch Med Res 2008; 39: 601–606.

Aapro

Caprariu

Chilingirov

, et al. Assessing the impact of antiemetic guideline compliance on prevention of chemotherapy-induced nausea and vomiting: results of the nausea/emesis registry in oncology (NERO). Eur J Cancer 2022; 166: 126–133.

Gilmore

Peacock

, et al. Antiemetic guideline consistency and incidence of chemotherapy-induced nausea and vomiting in US community oncology practice: INSPIRE study. J Oncol Pract 2014; 10: 68–74.

De Laurentiis

Bonfadini

Lorusso

, et al. Incidence of nausea and vomiting in breast cancer patients treated with anthracycline plus cyclophosphamide-based chemotherapy regimens in Italy: NAVY observational study. Support Care Cancer 2018; 26: 4021–4029.

Patil

Noronha

Joshi

, et al. Adherence to and implementation of ASCO antiemetic guidelines in routine practice in a tertiary cancer center in India. J Oncol Pract 2017; 13: e574–e581.

Patel

Robinson

Thackray

, et al. Guideline for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric cancer patients: a focused update. Pediatr Blood Cancer 2017; 64: 10.1002/pbc.26542.

Hesketh

Kris

Basch

, et al. Antiemetics: ASCO guideline update [published correction appears in J Clin Oncol. 2020 Nov 10;38(32):3825] [published correction appears in J Clin Oncol. 2021 Jan 1;39(1):96]. J Clin Oncol 2020; 38: 2782–2797.

Dupuis

Boodhan

Holdsworth

, et al. Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer 2013; 60: 1073–1082.

Patel

Robinson

Cohen

, et al. Prevention of acute and delayed chemotherapy-induced nausea and vomiting in pediatric cancer patients: a clinical practice guideline. Pediatr Blood Cancer 2022; 69: e30001.

10.

Pediatric Oncology Group of Ontario (POGO). Quick Review Summary: Guideline for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric patients. 2021 Jan, https://www.pogo.ca/wp-content/uploads/2021/01/Acute-AINV_Quick-Summary_15Jan2021_C.pdf

11.

Kovács

Wachtel

Basharova

, et al. Palonosetron versus ondansetron for prevention of chemotherapy-induced nausea and vomiting in paediatric patients with cancer receiving moderately or highly emetogenic chemotherapy: a randomised, phase 3, double-blind, double-dummy, non-inferiority study. Lancet Oncol 2016; 17: 332–344.

12.

Tan

Wang

Liang

, et al. Palonosetron is nonsuperior to ondansetron in acute phase but provides superior antiemetic control in delayed phase for pediatric patients administered highly emetogenic chemotherapy. Pediatr Blood Cancer 2018; 65: 10.1002/pbc.26815.

13.

Patel

Paw Cho Sing

Dupuis

. Safety of clinical practice guideline-recommended antiemetic agents for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric patients: a systematic review and meta-analysis. Expert Opin Drug Saf 2019; 18: 97–110.

14.

Dupuis

Alexander

Ali

, et al. Prevention of Chemotherapy or Radiotherapy-induced Nausea and Vomiting. The Hospital for Sick Children Departmental Guidelines (version 1) (2017).

15.

Flank

Robinson

Holdsworth

, et al. Guideline for the treatment of breakthrough and the prevention of refractory chemotherapy-induced nausea and vomiting in children with cancer. Pediatr Blood Cancer 2016; 63: 1144–1151.

16.

Dupuis

Boodhan

Sung

, et al. Guideline for the classification of the acute emetogenic potential of antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer 2011; 57: 191–198.

17.

Hesketh

Kris

Basch

, et al. Antiemetics: American society of clinical oncology clinical practice guideline update. J Clin Oncol 2017; 35: 3240–3261.

18.

Ettinger

Berger

Anand

, et al. Antiemesis. NCCN Clinical Practice Guidelines in Oncology. Version 1.2021 (2020), http://nccndd.qitian-med.tech/nccn-his/%E6%AD%A2%E5%90%90/%E6%AD%A2%E5%90%902021.1%E7%89%88.pdf

19.

Jordan

Chan

Gralla

, et al. 2016 Updated MASCC/ESMO consensus recommendations: emetic risk classification and evaluation of the emetogenicity of antineoplastic agents. Support Care Cancer 2017; 25: 271–275.

20.

Sugalski

Beauchemin

, et al. Facilitators and barriers to clinical practice guideline-consistent supportive care at pediatric oncology institutions: a children’s oncology group study. Implement Sci Commun 2021; 2: 106. Published 2021 Sep 16.

21.

Wright

Neugut

Ananth

, et al. Deviations from guideline-based therapy for febrile neutropenia in cancer patients and their effect on outcomes. JAMA Intern Med 2013; 173: 559–568.

22.

Aapro

Molassiotis

Dicato

, et al. The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the pan European emesis registry (PEER). Ann Oncol 2012; 23: 1986–1992.

23.

Dupuis

Alexander

Ali

, et al. Prevention of Chemotherapy or Radiotherapy-induced Nausea and Vomiting. The Hospital for Sick Children Departmental Guidelines (version 1) (2022).

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