Chemotherapy-Associated nausea and vomiting: A cross-sectional survey of occurrence and management patterns at jos university teaching hospital, Nigeria.

Background: The management patterns for chemotherapy-associated nausea and vomiting (CANV) in Sub-Saharan African settings have not been previously reported. The objectives of this study were to describe the prescribing pattern of antiemetics for CANV, to assess their adherence to guidelines, and to determine the occurrence of CANV. Subjects and
Methods: This was a cross-sectional study, with data extracted from the records of adult patients who received chemotherapy from 2015 to 2018 at Jos University Teaching Hospital, Nigeria. The National Comprehensive Cancer Network Harmonized Guidelines™ for Sub-Saharan Africa for Antiemesis Version 3.2018 was used to determine the extent of guideline adherence.
Results: Records of 165 patients were analyzed. Majority of the patients (76.4%, n = 126) received moderate-to-high emetic risk intravenous (IV) chemotherapy. Out of 129 antiemetic prescriptions for acute-phase prophylaxis, ondansetron (75.2%), corticosteroids (61.2%), and promethazine (24.8%) were the most prescribed agents. In the delayed phase, 50 patients received prophylactic antiemetics in the order of corticosteroids, ondansetron, and promethazine at 74%, 34%, and 26%, respectively. Guideline adherence was low for the acute-phase (23.6%), delayed-phase (20.6%), and overall period (17.6%). Among inpatients (n = 85), occurrences of nausea were negligible, whereas acute vomiting (9%) and delayed vomiting (15%) levels were considerable. Not receiving highly emetogenic IV chemotherapy was associated with significantly lower odds for nausea or vomiting occurrence, odds ratio 0.228 (95% confidence interval 0.054-0.967). Conclusions: Antiemetic guideline adherence was low due to antiemetic under-prescribing. A few nausea and vomiting events were recorded predominantly among patients who received highly emetogenic IV chemotherapy.

INTRODUCTION

Chemotherapy-associated nausea and vomiting (CANV) is a commonly occurring adverse event[1] that negatively impacts patients’ quality of life.[2] CANV occurs in the acute phase within 24-h postadministration of cancer chemotherapy or in the delayed phase, 2–5 days afterward.[3] If poorly managed, CANV could lead to dehydration, electrolyte disturbances,[4] and subsequent treatment delays with accumulating healthcare costs.

Depending on their emesis-inducing capacity, anticancer agents are classified into four categories namely highly emetogenic chemotherapy (HEC), moderately emetogenic chemotherapy (MEC), low emetogenic chemotherapy (LEC), and minimal emetic risk chemotherapy.[5] Studies indicate that more than 90% of patients experience acute vomiting with HEC in the absence of antiemetic prophylaxis.[5] Similarly, for MEC, LEC, and minimal emetic risk chemotherapy, the proportions of acute vomiting reported ranged from 30% to 90%, 10% to 30%, and <10%, respectively.[5]

The overarching goal of CANV control is prevention. Antiemetic agents used for CANV prophylaxis include neurokinin-1 receptor antagonists (NK-1RAs) exemplified by aprepitant, 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs) like ondansetron, the atypical antipsychotic drug olanzapine, and corticosteroids.[6] Guideline-recommended management of CANV entails administration of a three-drug combination of a 5-HT3RA, a corticosteroid, and an NK-1RA or olanzapine as acute-phase prophylaxis before administration of HEC.[7] A two-drug combination of a 5-HT3RA and a corticosteroid is considered sufficient acute-phase prophylaxis for MEC,[8] while a single antiemetic agent (5-HT3RA or corticosteroid) is adequate for LEC.[6] Acute-phase regimens may be augmented by the administration of prophylactic antiemetics for 2 or more days in the delayed phase for patients receiving HEC, MEC,[78] or multiday chemotherapy regimens.[6]

Research evidence suggests that guideline-recommended antiemetic management results in significantly better CANV control.[9] Despite this, a considerable proportion of patients at risk of CANV do not receive optimal antiemetic management. Nonadherence to antiemetic-prescribing guidelines appears to be widespread. While a European multicenter prospective study reported under-prescribing of antiemetic agents,[10] an American multicenter retrospective study reported overprescribing of antiemetic agents.[11] There is a paucity of literature on adherence to CANV management guidelines in Nigeria. Findings of a survey of oncology professionals suggest that inadequate facilities and complexity of guideline information were barriers to implementation of guidelines.[12] Therefore, the objectives of this study were to describe the prescribing pattern of antiemetics for CANV, to assess their adherence to guidelines, and to determine the occurrence of CANV.

SUBJECTS AND METHODS

Study design

A cross-sectional study was carried out at Jos University Teaching Hospital (JUTH), Jos, Plateau State, Nigeria.

Ethics

Ethical clearance (Ref: JUTH/DCS/ADM/127/XXVIII/1265) was obtained from the Institutional Health Research Committee of JUTH.

Patients

Records of all adult patients (≥18 years) who received at least one cycle of intravenous (IV) or oral chemotherapy from January 1, 2015, to December 31, 2018, were eligible for inclusion.

Data collection

Data were manually abstracted from the medical records into a data collection pro forma. Data collected included patients’ demographic data, baseline cancer clinical data, details of the chemotherapy regimen, antiemetic regimen, as well as occurrences of nausea and vomiting.

Chemotherapy agents prescribed were classified into IV single-day, IV multiday, or per-oral (PO) multiday, depending on the route and schedule of administration. Anticancer agents prescribed were classified according to the emetic risk classes following the criteria of the National Comprehensive Cancer Network (NCCN) Harmonized Guidelines™ for Sub-Saharan Africa for Antiemesis Version 3.2018 [Appendix 1].[6]

Appendix 1

Emetogenic potential of selected anticancer agents

Emetogenic potential	Intravenous agents
HEC (>90% frequency of emesis)	AC combination Cisplatin Cyclophosphamide >1500 mg/m2 Dacarbazine	Doxorubicin ≥60 mg/m2 Epirubicin >90 mg/m2 Ifosfamide ≥2 g/m2/dose
MEC (>30%-90% frequency of emesis)	Cyclophosphamide ≤1500 mg/m2 Cytarabine >200 mg/m2 Dactinomycin Daunorubicin Oxaliplatin	Doxorubicin <60 mg/m2 Epirubicin ≤90 mg/m2 Ifosfamide <2 g/m2/dose Melphalan Methotrexate ≥250 mg/m2
LEC (10%-30% frequency of emesis)	Cytarabine (low dose) 100-200 mg/m2 Docetaxel Doxorubicin (liposomal) 5-FU	Methotrexate >50 <250 mg/m2 Paclitaxel Gemcitabine Etoposide
Minimal* (<10% frequency of emesis)	Bleomycin Cytarabine <100 mg/m2 Methotrexate ≤50 mg/m2	Vinblastine Vincristine
Per-oral agents
MEC/HEC (≥30% frequency of emesis)	Cyclophosphamide (≥100 mg/m2/d)
Minimal*/LEC (<30% frequency of emesis)	Capecitabine Chlorambucil Cyclophosphamide (<100 mg/m2/d) Hydroxyurea Imatinib	Methotrexate Regorafenib Sorafenib Vemurafenib Melphalan

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology: Harmonized Guidelines™ for Sub-Saharan Africa for Antiemesis V.3.2018.[6] ©National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed March 18, 2020. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. *Minimal emetic risk chemotherapy. HEC=Highly emetogenic chemotherapy, MEC=Moderately emetogenic chemotherapy, LEC=Low emetogenic chemotherapy, 5-FU=5-fluorouracil

Outcome assessment

Study definition of guideline adherence closely followed the NCCN Harmonized Guidelines™ for Sub-Saharan Africa for Antiemesis version 3.2018[Appendix 2].[6] Prescribing specific antiemetic doses was not required for guideline adherence in line with the practice established in previous research and to allow for comparison with the past studies.[910] Prescriptions with the recommended antiemetics for the recommended days were considered guideline adherent. Patients for whom there was no indication for antiemesis and did not receive antiemetics were also counted as guideline adherent. Prescriptions lacking recommended antiemetics for the recommended days or those containing nonrecommended antiemetics were considered guideline nonadherent. Excessive antiemetic prescribing, defined as prescribing of antiemetics without indication, prescribing more antiemetic agents than recommended or prescribing antiemetics for longer than the recommended period, was considered guideline nonadherence. Overall period guideline adherence was achieved when a patient received guideline adherent antiemetic prescriptions on the recommended days of both the acute and delayed phases.

Appendix 2

Study definition of guideline adherence

Indication Single-day chemotherapy	Day 1 before chemotherapy	Days 2 onward
IV HEC	Olanzapine + corticosteroid + 5-HT3RA	Olanzapine on days 2-4
OR
	NK-1RA + corticosteroid+5-HT3RA	Corticosteroid on days 2-4 + aprepitant on days 2-3 (if aprepitant was used on day 1)
IV MEC	Corticosteroid + 5-HT3RA±olanzapine	Corticosteroid or 5-HT3RA on days 2-3 or olanzapine on days 2-3 if olanzapine was used on day 1
IV LEC	Corticosteroid or metoclopramide or 5-HT3RA or prochlorperazine	None
IV Minimal*	No routine prophylaxis
Multi-day chemotherapy
IV MEC/HEC	NK-1RA+5-HT3RA + corticosteroid	5-HT3RA + corticosteroid
On each day of chemotherapy administration
IV Minimal*/LEC	Corticosteroid or metoclopramide or 5-HT3RA or prochlorperazine
PO* MEC/HEC	PO ondansetron
PO* Minimal*/LEC	No routine prophylaxis

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology: Harmonized Guidelines™ for Sub-Saharan Africa for Antiemesis V.3.2018.[6] ©National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed March 18, 2020. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. *Minimal emetic risk chemotherapy. IV=Intravenous, HEC=Highly emetogenic chemotherapy, MEC=Moderately emetogenic chemotherapy, LEC=Low emetogenic chemotherapy, PO=Per-oral, 5-HT3RA=5-Hydroxytryptamine 3 receptor antagonists such as ondansetron and granisetron, NK-1RA=Neurokinin-1 receptor antagonists such as aprepitant

Nausea and/or vomiting were considered to have occurred only when they were recorded in the patient's file.

Data analysis

The sample size formula for proportions with a finite population correction was used to calculate sample size. Assuming the prevalence of antiemetic guideline adherence to be 50%, with a precision of 7.5% and 95% confidence level, a minimum sample size of 153 was required.[13]

The Statistical Package for the Social Sciences (SPSS) version 23 (IBM Corporation, Armonk, New York, United States) was used for data management.

The prescribing pattern of antiemetics was determined by counting the number of patients who received specific antiemetics and their combinations for prophylaxis. Antiemetics prescribed were matched with emetic risk of chemotherapy prescribed to show the indications for the antiemetics.

Guideline adherence was determined by counting the number of patients who received guideline adherent antiemetic prescriptions as prophylaxis for the acute-phase, delayed-phase, and overall period.

The number of patients who experienced nausea and/or vomiting was counted for inpatients only. Outpatients were excluded from this analysis because they were not available for observation; thus, records of CANV occurrence in the hours following chemotherapy administration could not be found.

Corresponding percentages were computed for all the frequencies.

The association between the emetic risk of chemotherapy prescribed and CANV occurrence (any nausea or vomiting event) was determined. Association between guideline adherence and CANV occurrence was also determined. The Pearson's Chi-square test for independence or the Fisher's exact test was used as appropriate. A multivariate logistic regression model was built with CANV occurrence as the dependent variable, whereas overall period antiemetic guideline adherence (dichotomous), IV HEC (dichotomous), sex, and age were included as the independent variables. Statistical significance was achieved at a two-sided P < 0.05.

RESULTS

A total population of 1418 patients had a presumed or confirmed cancer diagnosis, according to the records of the hospital within the study period. All of these were potential chemotherapy recipients. However, records of 706 patients could not be retrieved and only 712 records were available and assessed for eligibility. Of these, 547 did not receive chemotherapy and therefore were ineligible for inclusion in the study. Records of 165 patients who received chemotherapy were analyzed. Table 1 shows demographic and clinical characteristics of the study participants.

Table 1

Demographic and clinical characteristics of study patients (n=165)

	Frequency (%)
Mean patient age (years)±SD	47±14
Sex
Female	104 (63.0)
Male	61 (37.0)
Primary malignancy
Breast cancer	48 (29.1)
Leukemia	20 (12.1)
Colorectal cancer	18 (10.9)
Gestational trophoblastic neoplasms	11 (6.7)
Cervical cancer	9 (5.5)
Soft tissue sarcomas	8 (4.8)
Lymphomas	5 (3.0)
Gastric cancer	5 (3.0)
Rectoanal cancer	5 (3.0)
Other malignancies	36 (21.9)
Chemotherapy schedule type and route of administration
Single-day IV chemotherapy	112 (67.9)
Multiday IV chemotherapy	26 (15.8)
Multiday PO chemotherapy	27 (16.4)
Chemotherapy emetogenicity
IV HEC	86 (52.1)
IV MEC	40 (24.2)
IV LEC	11 (6.7)
IV Minimal*	1 (0.6)
PO MEC/HEC	6 (3.6)
PO Minimal*/LEC	21 (12.7)
Chemotherapy history
Chemotherapy naïve	150 (90.9)
Chemotherapy exposed	15 (9.1)
Admission status
Inpatients	85 (51.5)
Outpatients	80 (48.5)

*Minimal emetic risk chemotherapy. IV=Intravenous, PO=Per-oral, HEC=Highly emetogenic chemotherapy, MEC=Moderately emetogenic chemotherapy, LEC=Low emetogenic chemotherapy, SD=Standard deviation

Prophylactic antiemetic prescribing pattern

Out of the 165 patients analyzed, 129 patients (78.2%) and 50 patients (30%) received at least one prophylactic antiemetic agent in the acute-phase and delayed-phase, respectively. Figure 1 shows the percentage distribution of individual antiemetic agents prescribed.

Figure 1

Percentage distribution of antiemetic agents prescribed for acute phase and delayed phase chemotherapy-associated nausea and vomiting prophylaxis. Corticosteroids prescribed included dexamethasone, hydrocortisone and prednisolone

The combination of ondansetron and a corticosteroid was prescribed to 50 patients (38.8%) as antiemetic prophylaxis for the acute phase. Promethazine was prescribed with a corticosteroid to 21 patients (16.3%), whereas a three-drug combination of promethazine, a corticosteroid, and ondansetron was prescribed to five patients (3.9%) as acute-phase prophylaxis.

Among patients who received delayed-phase antiemetics (n = 50), the combination of promethazine and a corticosteroid was prescribed to 11 patients (22%) while five patients (10%) were prescribed for ondansetron with a corticosteroid.

Guideline adherence for chemotherapy-associated nausea and vomiting prophylaxis

The proportion of patients who received guideline adherent antiemetic prescriptions for prophylaxis was 23.6% (n = 39) for the acute-phase period, 20.6% (n = 34) for the delayed-phase period, and 17.6% (n = 29) for the overall period. Excessive antiemetic prescribing was observed in four patients (2.4%) in the acute phase and in three patients (1.8%) in the delayed phase. A total of 87 (64.0%) out of 136 patients who had an indication for delayed-phase antiemetic prophylaxis (single-day IV MEC or HEC; multiday IV MEC/HEC, minimal/LEC; multiday PO MEC/HEC) did not receive any antiemetics. Guideline adherence was high among patients who received IV or PO chemotherapy of minimal-to-low emetogenicity and low among patients who received IV or PO chemotherapy of moderate-to-high emetogenicity [Figure 2].

Figure 2

Percent antiemetic guideline adherence by emetogenicity of prescribed chemotherapy agents and for the total study sample. IV = Intravenous, PO = Per-oral, MEC = Moderately emetogenic chemotherapy, HEC = Highly emetogenic chemotherapy, LEC = Low emetogenic chemotherapy, Minimal = Minimal emetic risk chemotherapy

Overall guideline adherence was 12.9% for the inpatient subgroup (n = 85) and 22.5% for the outpatient subgroup (n = 80).

The major reasons for guideline nonadherence in the acute phase were nonprescribing of NK-1RAs for patients who received single-day IV HEC or multiday IV MEC/HEC (n = 103, 62.4%); nonprescribing of corticosteroids for patients who received single-day IV MEC/HEC, multiday IV MEC/HEC (52 patients, 31.5%); nonprescribing of 5-HT3RAs for patients who received single-day IV HEC or MEC, IV multiday MEC/HEC, or multiday PO MEC/HEC (41 patients, 24.8%).

In the delayed phase, guideline nonadherence was majorly due to nonprescribing of NK-1RAs for 86 patients (52.1%) who received single-day IV HEC; nonprescribing of corticosteroids for patients who received single-day IV HEC or multiday IV MEC/HEC (73 patients, 44.2%); nonprescribing of 5-HT3RAs for patients who received multiday IV MEC/HEC or multiday PO MEC/HEC (n = 23, 13.9%); nonprescribing of either a corticosteroid or a 5-HT3RAs for 18 patients (10.9%) who received single-day IV MEC.

Chemotherapy-associated nausea and vomiting occurrence

Only inpatients (n = 85) were included for analysis of CANV occurrence. Seventeen patients (20%) experienced at least one episode of nausea or vomiting. Acute nausea occurred in four patients only (5%), while acute vomiting occurred in eight patients (9%). Delayed nausea occurred in two patients (2%), while delayed vomiting was present in 13 patients (15%). Figure 3 shows the pattern of occurrence of various CANV categories. Receiving highly emetogenic IV chemotherapy was associated with higher CANV occurrence than receiving chemotherapy of other emetic risk classes (χ2 [1, N = 73] =5.0, P = 0.025). No association was found between overall guideline adherence and nonoccurrence of nausea or vomiting (P = 0.110, Fisher's exact test). On multivariate analysis, not receiving IV HEC was associated with significantly lower odds for CANV occurrence – odds ratio 0.228 (95% confidence interval 0.054–0.967; P = 0.045). Overall period guideline nonadherence was not significantly associated with CANV occurrence on multivariate analysis.

Figure 3

Occurrence of chemotherapy-associated nausea and vomiting for in-patients (n = 85)

DISCUSSION

In this study, the most prescribed antiemetic agents were ondansetron (75.2%), corticosteroids (61.2%), and promethazine (24.8%) for acute-phase prophylaxis; as well as corticosteroids (74%), ondansetron (34%), and promethazine (26%) for delayed-phase prophylaxis. Antiemetic guideline adherence was low for the acute-phase (23.6%), delayed-phase (20.6%), and overall periods (17.6%). Vomiting occurred in 9% and 15% of patients in the acute and delayed phases, respectively, while nausea occurrence both in the acute and delayed phases was very low (≤5%).

Despite the frequent prescribing of ondansetron and corticosteroids, a large proportion of patients did not receive these agents for acute- or delayed-phase prophylaxis, leading to low antiemetic guideline adherence and hence suboptimal CANV management. Observational studies carried out in India and South Korea have also reported higher prescribing rates for 5-HT3RAs and corticosteroids,[1415] than those observed in the current study. Inadequate clinician knowledge on antiemetic prescribing is thought to have contributed to this difference. Promethazine prescribing in the current study was high despite lack of guideline recommendations to support its use for prophylaxis.[6] Literature on prescribing of promethazine and other phenothiazines for CANV prophylaxis is scarce. Promethazine prescribing might have been high due to its relative low cost and availability as compared to other antiemetics.

The level of guideline adherence (17.6%) was low, indicating that transfer of guideline recommendations to practice was inadequate. Higher levels of guideline adherence ranging from 29% to 71% have been reported in the United States, Europe, and Iran.[9101617] Prescribing of NK-1RAs was relatively high in these studies and could have contributed to the observed difference in guideline adherence with the current study.

For patients who received single-day IV HEC or multiday IV MEC/HEC, guideline adherence and hence protection from CANV were very low because none of them were prescribed for NK-1RA or olanzapine. Aprepitant prescribing has been observed to be low in studies from Indian and Saudi Arabian tertiary centers, probably due to its high cost.[1819] Olanzapine has also been reported to be infrequently prescribed.[18] From a general perspective, the cost of olanzapine at the study site was relatively high and could have contributed to its low prescribing rate.

Conversely, guideline adherence for patients who received chemotherapy of minimal or low emetogenicity, who have little or no requirement for antiemetic prescribing, was very high. Tavernier et al. reported similar findings from a prospective study conducted in France.[16] Excessive prescribing of antiemetics in the current study was negligible unlike in reports from Japan and the United States where costly antiemetics were prescribed for patients who were receiving chemotherapy of low and minimal emetogenicity.[1120] Resources at the study site like other public hospitals in Sub-Saharan Africa tend to be scarce, hence the need to avoiding wasteful prescribing.

The proportion of patients who did not receive any antiemetic agent in the delayed phase despite having a clear indication for antiemesis was disproportionately high as compared to the acute phase. This shows that antiemetic prophylaxis for the delayed phase was neglected. A similar observation was made in an Italian multicenter prospective study where 30% of patients who needed antiemetics in the delayed phase did not receive any.[21]

The occurrence of both acute and delayed nausea was very low (≤5%). Previous research has shown that nausea is highly occurring (42%) in patients receiving MEC and higher emetic risk chemotherapy who constituted the majority of patients in the current study.[22] This study depended on archival records of clinicians’ assessment notes to pick out nausea events. It is therefore possible that clinicians may have not probed for the presence of nausea in their patients, leading to under-reporting. A prospective study where nausea events will be recorded in real-time is required to confirm this observation.

In contrast to nausea, the occurrence of vomiting in both the acute and delayed phases was considerable and shows the extent of patient suffering as a result of CANV. Previous studies report similar levels of vomiting.[2223] As compared to nausea, vomiting was identified more frequently in the current study although literature shows that nausea is in fact more frequently occurring,[222324] further supporting the hypothesis that nausea was under-reported.

Patients receiving IV HEC experienced significantly more CANV than patients receiving other types of chemotherapy underscoring the need for appropriate antiemetic prophylaxis for this patient population. This observation is consistent with what has been reported in the past research.[25]

Findings from this study suggest that antiemetic guideline adherence does not offer protection from CANV. However, prospective studies have shown that guideline adherence is associated with a significant reduction in CANV.[910] This difference in findings could be explained by the retrospective cross-sectional design used in the current study, in which a large number of CANV events could have been missed precluding a proper assessment of the effect of guideline adherence. A prospective study is required to shed light on the effect of antiemetic guideline adherence on nausea and vomiting occurrence in a similar setting as the current study.

Strengths and weaknesses

This study shows a real-world picture of antiemetic management practices among patients receiving chemotherapy of all emetic risk classes used in practice including chemotherapy of low emetogenicity and PO chemotherapy which have not received adequate research attention. A weakness of this study was the inability to accurately determine the occurrence of nausea which could be attributed to the cross-sectional retrospective design. Prospective studies are needed to address this shortcoming.

CONCLUSIONS

The levels of guideline adherence in antiemetic management were low due to under-prescribing of 5-HT3RAs and corticosteroids, nonprescribing of NK-1RAs and olanzapine, and a neglect of antiemetic prophylaxis in the delayed phase. Notably, promethazine prescribing was frequent while excessive antiemetic prescribing was negligible. While vomiting occurrences were substantial, occurrences of acute and delayed nausea may have been under-reported. Strategies to enhance transfer of guideline recommendations to practice which include clinician education and use of chemotherapy order templates with prespecified antiemetics are needed to help improve management of CANV.

Financial support and sponsorship

This research was supported by a postgraduate studentship grant from the World Bank Sponsored ACEPRD, University of Jos, Nigeria.

Conflicts of interest

There are no conflicts of interest.