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R Clin Pharm 2023; 1(2): 115-126

Published online December 31, 2023 https://doi.org/10.59931/rcp.23.030

Copyright © Asian Conference On Clinical Pharmacy.

Explore Chemotherapy-Induced Nausea and Vomiting Prophylaxis Patterns and Patient-Reported Events to Suggest Improvements in Patient Care in Oncology-Specialized Hospitals in Vietnam

Hanh T.H. Nguyen1 , Linh K. Duong1 , Tien D Vu2 , Thu T.M. Hoang2 , Duong V Bach3 , Hao T.L Hoang3 , Huong T.L. Nguyen1

1Department of Clinical Pharmacy, Hanoi University of Pharmacy, Hanoi, Vietnam
2Department of Pharmacy, Vietnam National Cancer Hospital, Hanoi, Vietnam
3Department of Pharmacy, Hanoi Oncology Hospital, Hanoi, Vietnam

Correspondence to:Huong T.L. Nguyen
E-mail Huongntl@hup.edu.vn
ORCID
https://orcid.org/0000-0002-8051-5017

Received: November 9, 2023; Revised: December 12, 2023; Accepted: December 13, 2023

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background: Chemotherapy-induced nausea and vomiting (CINV) is considered as the most distressing side effect of chemotherapy (CT). Overuse of prophylaxis leads to waste of resources, whereas underuse results in poor CINV prevention. Therefore, it is important to explore the pattern of CINV prophylaxis and CINV occurrence to improve the quality of medication use.
Methods: This prospective, observational study was conducted in two oncology-specialized hospitals in North Vietnam in 2019 to investigate the CINV prophylaxis regimens and CINV events among cancer patients receiving intravenous high-, moderate-, or lowemetic-risk CT (HEC, MEC, or LEC, respectively) after the administration of the first cycle of CT. The Multinational Association of Supportive Care in Cancer Antiemesis Tool was used to assess nausea and vomiting.
Results: The study included 294 patients (HEC: 224, MEC: 61, and LEC: 9). They were prescribed a similar pattern of prophylaxis for both acute and delayed emesis regardless of their emetic risks. Patient-specific factors, including sex, age, balance disorder, and comorbidity, but not the emetic risk of CT, were associated with the choice of prophylactic regimens. The incidence rate of CINV was 47.3% in all patients. Multivariate analysis revealed that HEC was associated with an increased risk of acute CINV compared with MEC (odds ratio, 2.34; 95% confidence interval, 1.03–5.32), whereas female sex and younger age were associated with a higher risk of delayed CINV.
Conclusion: CINV management is challenging and may involve over- and underuse of prophylaxis. A more effective approach to prophylaxis in the context of limited resources needs to be developed to improve patient outcomes.

KeywordsChemotherapy-induced nausea and vomiting; Prophylaxis; Patient care

Chemotherapy-induced nausea and vomiting (CINV) which are considered the most distressing side effects related to chemotherapy [1], would lead to deteriorate patients’ clinical outcomes (e.g., dehydration, electrolyte imbalances, weight loss, and malnourishment), and negatively impact their quality of life and daily activities [2,3]. These events would also result in additional supportive care, outpatient visits, or hospitalization, which might incur an economic burden [4]. Moreover, inadequate control of CINV could lead to patients’ delay or refusal of possible life-saving chemotherapy (CT) [5]. Although antiemetic medications have reduced the incidence of vomiting and nausea substantially, approximately 30% to 60% of patients still experienced acute or delayed nausea after chemotherapy [2]. This demonstrates a great challenge for healthcare professionals to prevent and treat CINV with available antiemetic agents in clinical practice settings, especially in limited-resource countries. Therefore, proper antiemetic use is claimed as one of the five key opportunities to improve care and reduce costs in cancer by the American Society of Clinical Oncology (ASCO) [6].

To foster the appropriate use of antiemetic medications in cancer patients treated with CT, the evidence-based guidelines for CINV prevention and treatment have been developed and updated by various cancer societies, e.g., ASCO, National Comprehensive Cancer Network (NCCN), Multinational Association of Supportive Care in Cancer and the European Society of Medical Oncology (MASCC and ESMO) [7-9]. As per their consensus, the prophylaxis of CINV with medications such as serotonin receptor antagonists (5-HT3RA), dexamethasone, neurokinin-1 receptor antagonists (NK1RA), and olanzapine, should be the primary goal and be implemented specifically for those patients treated with CT classified as highly emetogenic chemotherapies (HEC) [7-10]. Adherence to the guidelines demonstrated a strong correlation with the improvement of CINV control in PEER or INSPIRE studies with significant reductions in CINV incidences [11,12].

However, the use of antiemetic drugs for CINV was still an issue. In high-income countries, where mostly antiemetic medications are available, overuse was reported in 24.1% of patients of various CINV risk groups [13], and in up to 70% of patients receiving low-emetogenic chemotherapies (LEC) [6]. No prophylaxis or a lack of prophylactic duration were also reported as the main reasons for non-adherence to the clinical guidelines in these countries [11,12]. In resource-limited countries, it’s more challenging to follow the antiemetic guidelines, as it is presumed that “socio-economic status” is one of the rationales for non-adherence [14]. A study in Jordan showed that there were no NK1RA in the CINV prophylaxis therapy, and the prevalence of CINV was as high as more than 70% in the included patients [15]. In a study based on medication data in China, there was also a lack of NK1RA and an overutilization of the other antiemetic agents [16]. Therefore, it’s essential to reveal prophylactic problems to improve the practice of CINV prophylaxis and patient outcomes. In Vietnam, a resource-limited country, antiemetic medications were not available in full range, and information about CINV prophylaxis and its effectiveness was limited. Therefore, we conducted this study to investigate the patterns of CINV prophylaxis in Vietnam and patient-reported CINV events to explore the potential gap in practice. With that, we expected to propose measurements to use the limited healthcare resources optimally and to improve patient outcomes in the future.

Study Design, Settings and Patient Selection

This prospective, observational study was conducted at two oncology-specialized hospitals in North Vietnam from March 2019 to June 2019. Patients were eligible if they had a confirmed cancer diagnosis, were aged ≥18 years, and were scheduled to take the first cycle of a single-day, intravenous chemotherapy. The emetic risk of chemotherapy was classified as HEC, moderate emetogenic chemotherapy (MEC), and LEC according to the NCCN guidelines for anti-emesis version 2019.1 [17]. Patients who concurrently took (an) oral cytotoxic agent(s), used to be treated with chemotherapy, experienced nausea or vomiting in 24 hours before the administration of the chemotherapy, had brain metastases or bowel obstruction, or whose medical records were not accessed, were excluded.

Data Collection

Data collection consisted of medical record extraction and patient interviews. A form was created to retrieve data from medical records, which included patient demographic and clinical characteristics, the prescribed chemotherapy and medications for CINV prophylaxis, and other co-medications. The demographic and clinical characteristics consisted of age, gender, body weight and height, type of cancer, comorbidities, and the status of concurrent radiotherapy. The chemotherapy and all prescribed medications were recorded for their names and active ingredients, route of administration, dose, and duration. A questionnaire about risk factors for CINV, including history of balance disorder, motion sickness, nausea and vomiting related to pregnancy (if applicable), anxiety about chemotherapy, and frequency of alcohol drinking, was used to interview patients. The Multinational Association of Supportive Care in Cancer Antiemesis Tool (MAT), a validated tool to measure CINV, was used to assess patients’ experiences of the occurrence and severity of nausea and vomiting [18]. Permission to use MAT was granted by the Multinational Association of Supportive Care in Cancer (MASCC).

There was a pre-established process for data collection. Every day during the study period, the clinical pharmacists screened a list of patients admitted to the hospitals for those with the first cycle of chemotherapy. Their medical records were reviewed to select eligible patients for the study and to collect the data on the form. The selected patients were interviewed to obtain their risk factors for CINV and were introduced to MAT before or during their administration of chemotherapy. The time of the initiation of the chemotherapy administration was noted to identify the acute and delayed phases of CINV. The patients were approached twice, 24 hours and 120 hours after the chemotherapy, for their responses to MAT in the acute and delayed phases, respectively. The process is summarized in Fig. 1.

Figure 1. Patient recruitment flow.
MAT=The Multinational Association of Supportive Care in Cancer Antiemesis Tool.

Outcome Measure

The MAT used to evaluate patients’ experiences of nausea and vomiting consists of eight items. The first four are for nausea and vomiting for the acute phase, which is 24 hours following chemotherapy, and the last four items are for the delay phase, the period after that until 120 hours. In both phases, patients were asked whether they experienced nausea (items 3 and 7) and vomiting (items 1 and 5). They were asked about the severity of nausea (items 4 and 8) on a scale from 0 (no nausea) to 10 (as much as possible) and the number of vomiting episodes (items 2 and 6) [18]. In this study, the events of CINV were defined as severe if patients reported from four episodes of vomiting, or from level six of nausea in the questions about CINV severity in MAT.

Definition of Exposure

As for the 5-HT3RA, the upper limit of an agent’s daily dose recommended for the acute phase by NCCN [17], which were similar to those by ASCO, MASCC and ESMO [7-10], and was considered one recommended dose (RD). One RD of the locally available 5-HT3RA was 0.25 mg of intravenous (IV) palonosetron, 24 mg of oral ondansetron, 16 mg of IV ondansetron, or 1 mg of IV granisetron. If the 5-HT3RA daily dose of a patient was higher than one RD, it would be classified as a high dose of 5-HT3RA.

As the NCCN guidelines recommended that in prophylactic regimens with a NK1RA, the daily doses of dexamethasone are 12 mg and 8 mg for the acute and delayed phases, respectively, and higher glucocorticoid (GC) doses should be used when a NK1RA agent is not given concomitantly [17]. Therefore, the daily dose of GC was considered to be high if it was higher than 12 mg of dexamethasone for the acute phase and more than 8 mg of dexamethasone for the delayed phase. The GC included in the chemotherapy regimen was also calculated for the CINV prophylaxis.

The medications used on the day of CT were recorded for the acute phase (day 1), and those on the following days were for the delayed phase (from day 2 to day 4). Patients were considered to be covered by 5-HT3RA in the delayed phase if they were prescribed IV palonosetron on day 1 due to its long half-life [12].

Statistical Analyses

Patient demographic and clinical characteristics, risk factors were summarized using descriptive statistics. These factors, the pattern of prophylaxis, and the incidence of CINV were compared among groups of patients treated with HEC, MEC, and LEC using the Pearson Chi-square test or Fisher exact test for categorical variables and one way ANOVA for the continuous variables. The associations between demographics, clinical characteristics, risk factors, and the pattern of CINV prophylaxis were analyzed using χ2-test. The variable of emetic risks of CT but not cancer type was employed in the analysis because they are correlated, and the risk of CT was the primary criterion for CINV prophylactic regimen selection. The associations of the demographics and clinical characteristics, risk factors, the patterns of CINV prophylaxis with the occurrence of events in the acute and delayed phases were also examined using χ2-test. Then the factors that had the p-values less than 0.1 were included in the final logistic regression models (for bivariate outcome) or ordinal logistic regression model (for ordinal outcomes) to compute odds ratios and the corresponding 95% CI. The study was approved by Review board of Hanoi University of Pharmacy (Number 407/QD-DHN) and accepted by the study sites. Patients’ consents were obtained orally and by their agreement to join the interviews.

Demographic and Risk Factor Characteristics

The study included 294 patients in three groups: HEC, MEC, and LEC. The groups were significantly different in patients’ age, the frequent alcohol usage, the concomitant use of radiation therapy (RT), and the type of cancer (Table 1). The mean age was 54.4 years in the whole studied population, however, more patients under 60 years old were in the HEC group compared with MEC and LEC groups, 70.1% vs. 59.0% and 22.2% respectively (p=0.005). Patients treated with RT concurrently in HEC accounted for 33.0%, while it was 19.7% in MEC and 0% in LEC (p=0.02). In contrast, the proportion of patients with frequent use of alcohol was highest in the LEC group (55.6%) and they were quite similar in HEC and MEC groups (21.4% and 18.0%, respectively). Most of the patients had breast cancer (30.0%), digestive tract cancer (25.5%), or lung cancer (18.0%) of all patients. However, cancer diseases among the groups were significantly different (p<0.001).

Table 1 Patient demographics and clinical characteristics

Patient characteristics\NTotal (N=294)HEC (N=224)MEC
(N=61)
LEC
(N=9)
p-value
Age (year), mean (SD)54.4 (11.1)53.4 (10.7)56.6 (11.4)64.2 (13.7)0.003
Age <60 years old, n (%)195 (66.3)157 (70.1)36 (59.0)2 (22.2)0.005
BMI, n (%)0.13
<18.541 (13.9)29 (13.0)8 (13.1)4 (44.4)
18.5≤BMI<25226 (76.9)174 (77.7)48 (78.7)4 (44.4)
≥2527 (9.2)21 (9.4)5 (8.2)1 (11.1)
Female gender, n (%)171 (58.2)128 (57.1)39 (63.9)4 (44.4)0.44
Having comorbidity, n (%)100 (34.0)74 (33.0)23 (37.7)3 (33.3)0.79
Concurrent RT, n (%)86 (29.3)74 (33.0)12 (19.7)00.02
Nervousness before CT, n (%)15 (5.1)12 (5.4)3 (4.9)01.00
History of balance disorder, n (%)36 (12.2)31 (13.8)5 (8.2)00.26
History of carsick, n (%)103 (35.0)76 (33.9)26 (42.6)1 (11.1)0.14
History of nausea/vomit related to pregnancy, n (%)58 (19.7)42 (18.8)14 (23.0)2 (22.2)0.75
Frequent alcohol usage, n (%)64 (21.8)48 (21.4)11 (18.0)5 (55.6)0.04
Type of cancer, n (%)<0.0001
Breast cancer88 (30.0)61 (27.2)25 (41.0)2 (22.2)
Digestive tract cancer*75 (25.5)53 (23.7)22 (36.1)0
Lung cancer53 (18.0)44 (19.6)8 (13.1)1 (11.1)
Gynecologic cancer45 (15.3)41 (18.3)2 (3.3)2 (22.2)
Non-Hodgkin lymphoma17 (5.8)13 (5.8)4 (6.5)0
Others16 (5.4)12 (5.4)04 (44.5)

*Including tongue, nasopharyngeal, esophagus, gastric, colorectal cancer.

BMI=body mass index, CT=chemotherapy, HEC=high emetic risk chemotherapy, LEC=low emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, RT=radiotherapy, SD=standard deviation.


Patterns of CINV Prophylaxis

In the acute phase, a combination therapy of GC and 5-HT3RA was prescribed for all patients, regardless of the potential emetogenicity of the chemotherapy they used (Table 2). The proportions of patients treated with high doses of GC and 5-HT3RA were not significantly different among the groups (p=0.67 and 0.20, respectively). All patients with high doses of 5-HT3RA in this study used double the recommended doses.

Table 2 Pattern of prophylaxis for chemotherapy induced-nausea and vomiting

Pattern of CINV prophylaxis\NHEC (N=224)MEC (N=61)LEC (N=9)p-value
Acute phase - day 1
Prophylaxis therapy
GC+5HT3 RA224 (100.0)61 (100.0)9 (100.0)-
High dose of GC99 (44.2)24 (39.3)3 (33.3)0.67
High dose of 5-HT3 RA151 (67.4)34 (55.7)5 (55.6)0.20
Delayed phase - day 2
Prophylaxis therapy0.37
No use48 (21.4)14 (23.0)4 (44.4)
GC only23 (10.3)11 (18.0)1 (11.1)
5-HT3 RA only89 (39.7)19 (31.1)3 (33.3)
GC+5-HT3 RA64 (28.6)17 (27.9)1 (11.1)
High dose of GC11 (4.9)3 (4.9)0 (0)1.00
High dose of 5-HT3 RA29 (13.0)12 (19.7)1 (11.1)0.40
Delayed phase - day 3
Prophylaxis therapy0.10
No use124 (55.4)31 (50.8)8 (88.9)
GC only13 (5.8)6 (9.8)0 (0)
5-HT3 RA only70 (31.2)15 (24.6)0 (0)
GC+5-HT3 RA17 (7.6)9 (14.7)1 (11.1)
High dose of GC10 (4.5)1 (1.6)0 (0)0.62
High dose of 5-HT3 RA8 (3.6)7 (11.5)0 (0)0.06
Delayed phase - day 4
Prophylaxis therapy0.36
No use143 (63.8)45 (73.8)9 (100)
GC only9 (4.0)2 (3.3)0 (0)
5-HT3 RA only66 (29.5)13 (21.3)0 (0)
GC+5-HT3 RA6 (2.7)1 (1.6)0 (0)
High dose of GC8 (3.6)0 (0)0 (0)0.38
High dose of 5-HT3 RA3 (1.3)5 (8.2)0 (0)0.04

HEC=high emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, LEC=low emetic risk chemotherapy, GC=glucocorticoids, 5-HT3 RA=5-HT3 receptor antagonists.


In terms of prophylaxis for delayed nausea and vomiting, there was no statistically significant difference in the usage of anti-emesis medications for the patients in the groups from day 2 to day 4. The percentages of patients without prophylaxis increased from day 2 to day 4 (21.4%, 55.4% and 63.8% of the patients with HEC, respectively, and 23.0%, 50.8% and 73.8% of those with MEC, respectively). The proportion of the patients in HEC group treated with the combination of GC and 5-HT3RA was 28.6% on day 2 and decreased to 2.7% on day 4. Whereas 49.1% and 34.4% of the patients in MEC, were prophylactic with either GC or 5-HT3RA on day 2 and 3 respectively. The proportions of patients with high dose GC were under 5% across the groups of all the days.

Factors Associated with the Patterns of CINV Prophylaxis

The body mass index (BMI) equal or greater than 25 was the only factor related to the choice of high dose GC in the acute phase with OR=0.3 (0.10–0.87) compared to BMI less than 18.5 (Table 3). Fewer female than male patients were prescribed 5-HT3RA at the high dose in the acute phase (OR=0.42, 95% CI=0.02–0.87). However, the female patients were 2.47 times more likely to be treated enough or more days for the delayed prophylaxis than their male counterparts. They also tended to be treated with more drugs than men during the delayed phase, but were not significantly different. The patients having history of balance disorder were less likely to be treated enough or more days for the delayed prophylaxis (OR=0.4, 95% CI=0.17–0.91), while those with comorbidity were indicated two medications less frequent than the patients without comorbidity (OR=0.39, 95% CI=0.19–0.80).

Table 3 Multi-variable analysis for factors associated with the pattern of CINV prophylaxis

FactorsAcute phaseDelayed phase
High dose of GC*High dose of 5-HT3 RA*More or enough days of delayed prophylaxis*Number of drugs selection#
2 drugs
(5-HT3 RA and GC) vs. no use
1 drug
(5-HT3 RA or GC) vs. no use
Emetic risk of CT----
HEC0.64 (0.35-1.17)
MEC1
LECNE
Female gender (yes vs. no)-0.42 (0.20-0.87)2.47 (1.29-4.75)1.38 (0.64-2.98)1.92 (0.96-3.85)
Age <60 years old (yes vs. no)-0.57 (0.32-0.99)---
Concurrent RT (yes vs. no)-1.69 (0.92-3.10)1.03 (0.57-1.85)--
Nervousness before CT
(yes vs. no)
-----
History of balance disorder
(yes vs. no)
--0.40 (0.17-0.91)--
History of carsick (yes vs. no)-0.92 (0.51-1.64)1.25 (0.69-2.26)1.10 (0.47-2.59)1.35 (0.64-2.86)
History of nausea/vomit related to pregnancy (yes vs. no)--1.23 (0.63-2.40)--
Frequent alcohol usage
(yes vs. no)
-1.24 (0.53-2.93)---
Having comorbidity (yes vs. no)---0.39 (0.19-0.80)0.78 (0.42-1.43)
BMI----
<18.51
18.5≤BMI<250.65 (0.33-1.27)
≥250.30 (0.10-0.87)

Values are presented as odds ratio (95% confidence interval).

*Multi-variable logistic regression model including variables with p<0.1 in univariate analysis, #multi-variable ordinal regression model including variables with p<0.1 in univariate analysis. -variables tested in univariate analysis that had p-values ≥0.1.

CINV=chemotherapy induced nausea and vomiting, OR=odds ratio, CI=confident interval, GC=glucocorticoids, 5-HT3 RA=5-HT3 receptor antagonists, CT=chemotherapy, HEC=high emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, LEC=low emetic risk chemotherapy, NE=not estimated due to no event in the group, RT=radiotherapy, BMI=body mass index.


CINV Incidence and its Associated Factors

CINV happened in 20.8% and 46.4% of the patients in the acute and delayed phase respectively, and 47.3% experienced CINV in either phase (Table 4). The incidence of nausea was higher than of vomiting in both phases, and the delayed events happened more frequently than the acute ones in all categories. When comparing amongst groups of emetic risk, the higher risk groups had the higher incidences of the events with significant difference in some types of events such as: all CINV (p=0.01), all delayed CINV (p=0.04) and severe delayed CINV (p=0.02) (Table 4).

Table 4 CINV incidences and the comparison among emetogenic risk groups

CINV\NTotal (n=294)HEC (n=224)MEC (n=61)LEC (n=9)p-value
All CINV139 (47.3)116 (51.8)22 (36.1)1 (11.1)0.01
All acute CINV61 (20.8)53 (23.7)8 (13.1)00.06
Acute vomiting29 (9.9)25 (11.2)4 (6.6)00.34
Acute nausea60 (20.4)52 (23.2)8 (13.1)00.07
Severe acute CINV31 (10.5)27 (12.1)4 (6.6)00.27
Severe acute vomiting18 (6.1)16 (7.1)2 (3.3)00.65
Severe acute nausea28 (9.5)25 (11.2)3 (4.9)00.21
All delayed CINV#131 (46.4)108 (50.0)22 (37.9)1 (12.5)0.04
Delayed vomiting72 (25.5)62 (28.7)10 (17.2)00.05
Delayed nausea125 (44.3)103 (47.7)21 (36.2)1 (12.5)0.06
Severe delayed CINV#69 (23.5)61 (28.2)8 (13.8)00.02
Severe delayed vomiting35 (12.4)30 (13.9)5 (8.6)00.31
Severe delayed nausea57 (20.2)50 (23.2)7 (12.1)00.06

#There were 282, 216, 61 and 8 patients in total, HEC, MEC and LEC group respectively because some patients were lost to contact in the delayed phase.

CINV=chemotherapy induced nausea and vomiting, HEC=high emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, LEC=low emetic risk chemotherapy.


The multiple logistic regression analysis showed that patients treated with HEC was the only factor related to the 2.34 times higher risk of developing acute CINV than with MEC (OR=2.34 95% CI=1.03–5.32). Whereas HEC also tended to have more delayed CINV but non-significantly after controlling other factors. Female gender was associated with higher risk of acute and delayed CINV but only statistically significant in two models of delayed CINV (Table 5). For the risk of delayed CINV, in the model 1, besides gender, the occurrence of acute CINV increased the risk of delayed events by 10.26 times (95% CI=4.45–23.63). In the model 2, which excluded the patients with acute CINV, younger age was an additional factor associated with the increased risk of the event by 2.08 times (95% CI=1.07–4.07) after controlling for the others.

Table 5 Multivariate logistic regression analysis for acute and delayed CINV

Factors\NAcute CINV* (N=294)Delayed CINV
Model 1*,# (N=282)Model 2*,$ (N=221)
Emetic risk of CT
HEC2.34 (1.03-5.32)1.47 (0.74-2.90)1.87 (0.88-3.96)
MEC111
LECNE0.44 (0.05-4.27)0.45 (0.04-4.83)
Female gender (yes vs. no)1.95 (0.902-4.21)3.22 (1.41-7.33)3.38 (1.38-8.28)
Age <60 years old (yes vs. no)-1.76 (0.96-3.22)2.08 (1.07-4.07)
Concurrent RT (yes vs. no)---
Nervousness before CT (yes vs. no)---
History of balance disorder (yes vs. no)---
History of carsick (yes vs. no)1.57 (0.80-3.10)1.18 (0.61-2.29)1.19 (0.58-2.44)
History of nausea/vomiting related to pregnancy (yes vs. no)1.34 (0.65-2.76)1.36 (0.64-2.91)1.97 (0.86-4.54)
Frequent alcohol usage (yes vs. no)-1.56 (0.65-3.73)1.32 (0.50-3.52)
Having comorbidity (yes vs. no)---
BMI (18.5≤ BMI<25, ≥25 vs. <18)---
High dose of acute GC (yes vs. no)---
High dose of 5-HT3RAs in the acute phase (yes vs. no)---
Days of delayed CINV prophylaxisNT--
Therapy selectionNT--
No used1-
1 drug1.74 (0.78-3.88)1.41 (0.60-3.33)
2 drugs1.17 (0.56-2.44)0.85 (0.38-1.88)
Occurrence of acute CINVNT10.26 (4.45-23.63)NT

Values are presented as odds ratio (95% confidence interval).

*Multi-variable logistic regression model including variables with p<0.1 in univariate analysis, #Model included all patients with available information for delayed CINV (N=282), $Model excluded patients with acute CINV (N=221), -variables tested in univariate analysis that had p-values ≥0.1.

CINV=chemotherapy induced nausea and vomiting, OR=odds ratio, CI=confident interval, CT=chemotherapy, HEC=high emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, LEC=low emetic risk chemotherapy, NE=not estimated due to no event in the group. RT=radiotherapy, BMI=body mass index, GC=glucocorticoids, 5-HT3 RA=5-HT3 receptor antagonists, NT=not tested in univariate and multivariate analysis.

Although there were international and local emetic prophylaxis guidelines for patients receiving chemotherapy, we could not evaluate the adherence to these because of the lack of preventive medications (NK1RA) and the non-updated local guidelines [19]. However, this study revealed that the prophylactic patterns had the potential for both overuse and underuse. Underuse, i.e., lack of medication or insufficient doses according to the recommendations of the clinical guidelines, such as the ASCO, NCCN, and MASCC and ESMO guidelines for CINV prevention and treatment, may result in suboptimal patient outcomes, specifically nausea and vomiting, which occurred in approximately half of the included patients in the current study. Overuse, or the use of a medication not recommended by the guidelines mentioned above or at a higher dose than the recommended one, may lead to adverse effects and a waste of resources that could be allocated to better choices.

The patients in the HEC group were supposed to have more aggressive treatment. However, the prophylaxis patterns of the group did not differ from the other two groups MEC and LEC (Table 2), and the emetic risks of CT were not associated with physicians’ decisions about the anti-emesis drug selection, doses and durations of treatment (Table 3). Even patients in the HEC group seemed to have more other risk factors for nausea and vomiting such as concurrently treated with RT, younger age, and without the habit of consuming alcohol frequently [20,21].These results demonstrated a potential for improper CINV prophylaxis in the study.

Due to the unavailability of NK1RA in Vietnam, the prophylaxis for patients treated with HEC might be more likely to be insufficient. Olanzapine, which could be a choice according to the international guidelines, was not used in the study. A higher dose of GC, which was recommended in case of no NK1RA [9,17], was prescribed in 44.2% of the patients in the acute phase and in less than 5% in the delayed phase. The lack of prophylaxis for the delayed phase could also be seen in patients with no prevention medication in HEC group (21.4% on day 2, 55.4% on day 3 and 63.8% on day 4) and MEC groups (23.0% and 50.8% on day 2 and 3, respectively), or low proportion of patients in HEC having combination therapy.

Olanzapine was not utilized, which could be due to its weak evidence and the fear of its side effects such as QT prolongation (especially when combined with a 5-HT3RA). Moreover, olanzapine was not yet in the local guideline for CINV prophylaxis and it did not have the indication in the label. As a result, it was not covered by insurance, which could be a barrier to the usage. However, olanzapine did not cost much for several days and could be an acceptable solution for several specific patients receiving HEC. Ideally, the local guideline should be updated with taking olanzapine into consideration.

Another resolution for the lack of NK1RA was a higher dose of GC. However, HEC was not shown to relate with the choice of high dose GC in this study. The median dose of GC in the patients with high dose was still low (16 mg, IQR: 16–20 mg) for the acute phase, comparing with the recommendation of 20 mg in the local or ESMO guideline in the absence of NK1RA [9,19]. Therefore, high dose GC in this study did not show relation to the patients’ outcomes. This practice still gave a room to improve the clinical outcomes by using a higher dose of GC for patients with HEC.

In contrast, there was still a potential overuse of prophylactic medications. It was seen in the use of combination therapy in 100% of patients with LEC on day 1, and in 27.9% and 14.7% of patients with MEC on days 2 and 3, respectively, where a single drug of GC or a 5-HT3RA is recommended. The use of a high dose of 5-HT3RAs for the acute phase in 55.6% to 67.4% of patients in all groups was also a source of wasting. The high doses of 5-HT3RAs in this study were almost double those in the international guidelines. Although these guidelines are similar for 5-HT3RA dose recommendations [9,17], the local guidelines do not provide guidance on the doses, which could be a difficulty for physicians [19]. The prices for one-day treatment of these medications are usually 5–10 times higher than those of GC or olanzapine, according to the prices on the website of Drug Administration of Vietnam [22]. A high dose of 5-HT3RA also did not relate to the decrease in CINV occurrence in this study. Therefore, to save resources, the selection or dose of 5-HT3RA should be considered carefully.

In the current study, gender was a factor related to many aspects of CINV prophylaxis therapy, which could be understandable. Female patients, who are associated with a higher risk of CINV occurrence [20,21], were more likely to be treated with more drugs or for a longer duration in the delayed phase than their male counterparts. However, they were less likely to be prescribed high doses of 5-HT3RA, which could be explained by the fact that physicians may be more careful with the adverse effects of 5-HT3RA such as QT prolongation and torsade point, which are more likely to happen in women. In contrast, the potential emetogenicity of CT, which is usually the basis for choosing the therapy in the evidence guidelines, was not shown to be associated with the CINV prophylaxis patterns. Besides, patients with other risk factors for CINV, including younger age and a history of balance disorder [20,21], were chosen for less intensive therapy in the current study. These findings supported the aforementioned results that no difference in the prophylactic patterns among the LEC, MEC, and HEC groups was seen.

The incidences of different types of CINV showed the higher proportions in the higher emetic risk groups with significant differences (for all CINV: p=0.01, delayed CINV: p=0.04 or severe delayed CINV: p=0.02). This is understandable due to the similar patterns of prophylaxis among the three groups. Results from the regression analysis also confirmed these findings by showing the increased risk of developing CINV in HEC group in both the acute and delayed phase after controlling for other factors, although it did not show significantly different in the delayed phase. In the model 1 of the delayed phase, experiences of CINV in the acute phase increased the risk of delayed event by 10.26 times, which also meant an indirect relation of HEC to the delayed events. From these results, we raise the importance of following the practice guidelines, which are all based majorly on the emetic risk of CT.

Beside the emetic risk of CT, from multivariable logistic regression analysis, we found female gender and younger age were associated with both acute and delayed events. These findings were consistent with previous studies [20,23,24]. Recently, the prediction models of CINV risk have been developed taking into account patients’ factors for appropriate choices of antiemetics [25,26].

About the incidence of CINV, it was 47.3% in the current study, meaning that 52.7% patients did not experience any CINV. This rate was lower than that reported in a study conducted in 6 Asia Pacific countries in 2014 of which the complete response rate was 69% [27]. However, it was similar to the findings of a study in 8 European countries in 2010 which showed that the proportion of no CINV in the first cycle were 50.7% and 59.9% in the groups of non-adherence and adherence to anti emesis guidelines respectively [11]. At that time NK1RA and olanzapine had not yet been recommended in the ESMO guideline [10].

When looking at nausea and vomiting separately, the incidences of nausea were higher in both acute and delayed phases in the current study, 20.4% vs. 9.9% and 42.5% vs. 24.5% respectively, which showed that nausea was more difficult to control than vomiting. These patterns were similar to those in the recent studies in Korea and Jordan. In the Korean study, the rates of nausea in the acute and delayed phases were much higher than ours (46% and 83% respectively), while those of acute and delayed vomiting were quite similar (8.3% and 23%, respectively) [28]. However, the patients in that study received HEC and MEC only. In Jordan where NK1RA and olanzapine were not prescribed in the prophylaxis like the practice in ours, nausea and vomiting were at higher rates, about 60% and 42% respectively in acute phase, and similarly in the delayed phase [15].

Although this current study revealed the situation of CINV prophylaxis and patients’ outcomes, it had some limitations to be acknowledged. First, it only recorded the prescribed preventive medications for the patients to use at the hospitals and to take home after their CT administration. During the delayed phase at home, whether they took the medication and whether their medication were changed due to the occurrence of CINV were not studied. Therefore, it might interfere the effects of the prophylaxis regimens on CINV occurrence and severity. However, the description of the patterns of CINV prophylaxis still reflected the reality of the current practice, which was the main objective of this study. Second, the disparity in the number of patients among groups of CINV risks (HEC, MEC, and LEC) and their characteristics could affect the comparisons among the groups. This limitation is due to the nature of the cross-sectional study design used in this study, which is not allowed to allocate or match patients among groups. Third, this study did not consider physicians’ prescribing behaviors, which could also contribute to the pattern of CINV prophylaxis, especially the overuse in LEC and MEC groups and the underuse in HEC. Future research, including physician interviews about their prescribing behaviors, is needed to explore underlying reasons.

In conclusion, the pattern of CINV prophylaxis in this study showed a potential over- and under-use of anti-emesis medication. Emetic risk of CT has not yet been a key factor to consider a pattern of CINV prophylaxis, and CT with higher emetic risk was associated with higher possibility of developing CINV. While the resource was limited, more effort should be made to allocate the current resources effectively by taking into account the aspects recommended in the reputed guidelines such as emetic risk of CT and doses of medications. Ideally, an up-to-date local guideline should be established based on local resources, the available data and the international evidence-based guidelines to standardize the practice.

In conclusion, the pattern of CINV prophylaxis in this study showed a potential over- and under-use of anti-emesis medication. Emetic risk of CT has not yet been a key factor to consider a pattern of CINV prophylaxis, and CT with higher emetic risk was associated with higher possibility of developing CINV. While the resource was limited, more effort should be made to allocate the current resources effectively by taking into account the aspects recommended in the reputed guidelines such as emetic risk of CT and doses of medications. Ideally, an up-to-date local guideline should be established based on local resources, the available data and the international evidence-based guidelines to standardize the practice.

We would like to thank the participants who generously agreed to participate in the study and the pharmacy students who facilitated recruitment to this study. We also appreciate the thorough support of the participant hospitals, which allowed us to collect sufficient data for this study.

No potential conflict of interest relevant to this article was reported.

  1. de Boer-Dennert M, de Wit R, Schmitz PI, et al. Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer 1997; 76(8):1055-61.
    Pubmed KoreaMed CrossRef
  2. Cohen L, de Moor CA, Eisenberg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007 May; 15(5):497-503.
    Pubmed CrossRef
  3. Bloechl-Daum B, Deuson RR, Mavros P, Hansen M, Herrstedt J. Delayed nausea and vomiting continue to reduce patients' quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment. J Clin Oncol. 2006 Sep 20; 24(27):4472-8.
    Pubmed CrossRef
  4. Schwartzberg L, Harrow B, Lal LS, Radtchenko J, Lyman GH. Resource utilization for chemotherapy-induced nausea and vomiting events in patients with solid tumors treated with antiemetic regimens. Am Health Drug Benefits. 2015 Jul-Aug; 8(5):273-82.
  5. Schnell FM. Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. Oncologist 2003; 8(2):187-98.
    Pubmed CrossRef
  6. Schleicher SM, Bach PB, Matsoukas K, Korenstein D. Medication overuse in oncology: current trends and future implications for patients and society. Lancet Oncol. 2018 Apr; 19(4):e200-8.
    Pubmed CrossRef
  7. Razvi Y, Chan S, McFarlane T, et al. ASCO, NCCN, MASCC/ESMO: a comparison of antiemetic guidelines for the treatment of chemotherapy-induced nausea and vomiting in adult patients. Support Care Cancer. 2019 Jan; 27(1):87-95.
    Pubmed CrossRef
  8. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017 Oct 1; 35(28):3240-61.
    Pubmed CrossRef
  9. Roila F, Molassiotis A, Herrstedt J, et al; participants of the MASCC/ESMO Consensus Conference Copenhagen 2015. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol. 2016 Sep; 27(Suppl 5):v119-33.
    Pubmed CrossRef
  10. Navari RM, Aapro M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med. 2016 Apr 7; 374(14):1356-67.
    Pubmed CrossRef
  11. Aapro M, Molassiotis A, Dicato M, et al; PEER Investigators. The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol. 2012 Aug; 23(8):1986-92.
    Pubmed CrossRef
  12. Gilmore JW, Peacock NW, Gu A, et al. Antiemetic guideline consistency and incidence of chemotherapy-induced nausea and vomiting in US community oncology practice: INSPIRE Study. J Oncol Pract. 2014 Jan; 10(1):68-74.
    Pubmed CrossRef
  13. Encinosa W, Davidoff AJ. Changes in antiemetic overuse in response to choosing wisely recommendations. JAMA Oncol. 2017 Mar 1; 3(3):320-6.
    Pubmed CrossRef
  14. Andreae MH, Gabry JS, Goodrich B, White RS, Hall C. Antiemetic prophylaxis as a marker of health care disparities in the National Anesthesia Clinical Outcomes Registry. Anesth Analg. 2018 Feb; 126(2):588-99.
    Pubmed KoreaMed CrossRef
  15. Al Qadire M. Chemotherapy-induced nausea and vomiting: incidence and management in Jordan. Clin Nurs Res. 2018 Jul; 27(6):730-42.
    Pubmed CrossRef
  16. Zong X, Zhang J, Ji X, Gao J, Ji J. Patterns of antiemetic prophylaxis for chemotherapy-induced nausea and vomiting in China. Chin J Cancer Res. 2016 Apr; 28(2):168-79.
    Pubmed KoreaMed CrossRef
  17. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology (2019) antiemetics. Version 1 [Internet]. Plymouth Meeting, PA: NCCN [cited 2019 Feb 28]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf
  18. Molassiotis A, Coventry PA, Stricker CT, et al. Validation and psychometric assessment of a short clinical scale to measure chemotherapy-induced nausea and vomiting: the MASCC antiemesis tool. J Pain Symptom Manage. 2007 Aug; 34(2):148-59.
    Pubmed CrossRef
  19. Ministry of Health. Technical process of specialized medical examination and treatment in oncology.
  20. Sekine I, Segawa Y, Kubota K, Saeki T. Risk factors of chemotherapy-induced nausea and vomiting: index for personalized antiemetic prophylaxis. Cancer Sci. 2013 Jun; 104(6):711-7.
    Pubmed KoreaMed CrossRef
  21. Mosa ASM, Hossain AM, Lavoie BJ, Yoo I. Patient-related risk factors for chemotherapy-induced nausea and vomiting: a systematic review. Front Pharmacol. 2020 Apr 1; 11:329.
    Pubmed KoreaMed CrossRef
  22. Drug Administration of Vietnam. Drug bank [Internet]. Hanoi: Ministry of Health [cited 2023 Sep 19]. Available from: https://drugbank.vn/tim-kiem?search=ondansetron&entity=tenThuoc&page=1&size=12
  23. Tamura K, Aiba K, Saeki T, et al; CINV Study Group of Japan. Testing the effectiveness of antiemetic guidelines: results of a prospective registry by the CINV Study Group of Japan. Int J Clin Oncol. 2015 Oct; 20(5):855-65.
    Pubmed CrossRef
  24. Tsuji D, Suzuki K, Kawasaki Y, et al. Risk factors associated with chemotherapy-induced nausea and vomiting in the triplet antiemetic regimen including palonosetron or granisetron for cisplatin-based chemotherapy: analysis of a randomized, double-blind controlled trial. Support Care Cancer. 2019 Mar; 27(3):1139-47.
    Pubmed CrossRef
  25. Molassiotis A, Stamataki Z, Kontopantelis E. Development and preliminary validation of a risk prediction model for chemotherapy-related nausea and vomiting. Support Care Cancer. 2013 Oct; 21(10):2759-67.
    Pubmed CrossRef
  26. Dranitsaris G, Molassiotis A, Clemons M, et al. The development of a prediction tool to identify cancer patients at high risk for chemotherapy-induced nausea and vomiting. Ann Oncol. 2017 Jun 1; 28(6):1260-7.
    Pubmed KoreaMed CrossRef
  27. Hsieh RK, Chan A, Kim HK, et al. Baseline patient characteristics, incidence of CINV, and physician perception of CINV incidence following moderately and highly emetogenic chemotherapy in Asia Pacific countries. Support Care Cancer. 2015 Jan; 23(1):263-72.
    Pubmed CrossRef
  28. Rha SY, Park Y, Song SK, Lee CE, Lee J. Controlling chemotherapy-induced nausea requires further improvement: symptom experience and risk factors among Korean patients. Support Care Cancer. 2016 Aug; 24(8):3379-89.
    Pubmed CrossRef

Article

Original Article

R Clin Pharm 2023; 1(2): 115-126

Published online December 31, 2023 https://doi.org/10.59931/rcp.23.030

Copyright © Asian Conference On Clinical Pharmacy.

Explore Chemotherapy-Induced Nausea and Vomiting Prophylaxis Patterns and Patient-Reported Events to Suggest Improvements in Patient Care in Oncology-Specialized Hospitals in Vietnam

Hanh T.H. Nguyen1 , Linh K. Duong1 , Tien D Vu2 , Thu T.M. Hoang2 , Duong V Bach3 , Hao T.L Hoang3 , Huong T.L. Nguyen1

1Department of Clinical Pharmacy, Hanoi University of Pharmacy, Hanoi, Vietnam
2Department of Pharmacy, Vietnam National Cancer Hospital, Hanoi, Vietnam
3Department of Pharmacy, Hanoi Oncology Hospital, Hanoi, Vietnam

Correspondence to:Huong T.L. Nguyen
E-mail Huongntl@hup.edu.vn
ORCID
https://orcid.org/0000-0002-8051-5017

Received: November 9, 2023; Revised: December 12, 2023; Accepted: December 13, 2023

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background: Chemotherapy-induced nausea and vomiting (CINV) is considered as the most distressing side effect of chemotherapy (CT). Overuse of prophylaxis leads to waste of resources, whereas underuse results in poor CINV prevention. Therefore, it is important to explore the pattern of CINV prophylaxis and CINV occurrence to improve the quality of medication use.
Methods: This prospective, observational study was conducted in two oncology-specialized hospitals in North Vietnam in 2019 to investigate the CINV prophylaxis regimens and CINV events among cancer patients receiving intravenous high-, moderate-, or lowemetic-risk CT (HEC, MEC, or LEC, respectively) after the administration of the first cycle of CT. The Multinational Association of Supportive Care in Cancer Antiemesis Tool was used to assess nausea and vomiting.
Results: The study included 294 patients (HEC: 224, MEC: 61, and LEC: 9). They were prescribed a similar pattern of prophylaxis for both acute and delayed emesis regardless of their emetic risks. Patient-specific factors, including sex, age, balance disorder, and comorbidity, but not the emetic risk of CT, were associated with the choice of prophylactic regimens. The incidence rate of CINV was 47.3% in all patients. Multivariate analysis revealed that HEC was associated with an increased risk of acute CINV compared with MEC (odds ratio, 2.34; 95% confidence interval, 1.03–5.32), whereas female sex and younger age were associated with a higher risk of delayed CINV.
Conclusion: CINV management is challenging and may involve over- and underuse of prophylaxis. A more effective approach to prophylaxis in the context of limited resources needs to be developed to improve patient outcomes.

Keywords: Chemotherapy-induced nausea and vomiting, Prophylaxis, Patient care

Body

Chemotherapy-induced nausea and vomiting (CINV) which are considered the most distressing side effects related to chemotherapy [1], would lead to deteriorate patients’ clinical outcomes (e.g., dehydration, electrolyte imbalances, weight loss, and malnourishment), and negatively impact their quality of life and daily activities [2,3]. These events would also result in additional supportive care, outpatient visits, or hospitalization, which might incur an economic burden [4]. Moreover, inadequate control of CINV could lead to patients’ delay or refusal of possible life-saving chemotherapy (CT) [5]. Although antiemetic medications have reduced the incidence of vomiting and nausea substantially, approximately 30% to 60% of patients still experienced acute or delayed nausea after chemotherapy [2]. This demonstrates a great challenge for healthcare professionals to prevent and treat CINV with available antiemetic agents in clinical practice settings, especially in limited-resource countries. Therefore, proper antiemetic use is claimed as one of the five key opportunities to improve care and reduce costs in cancer by the American Society of Clinical Oncology (ASCO) [6].

To foster the appropriate use of antiemetic medications in cancer patients treated with CT, the evidence-based guidelines for CINV prevention and treatment have been developed and updated by various cancer societies, e.g., ASCO, National Comprehensive Cancer Network (NCCN), Multinational Association of Supportive Care in Cancer and the European Society of Medical Oncology (MASCC and ESMO) [7-9]. As per their consensus, the prophylaxis of CINV with medications such as serotonin receptor antagonists (5-HT3RA), dexamethasone, neurokinin-1 receptor antagonists (NK1RA), and olanzapine, should be the primary goal and be implemented specifically for those patients treated with CT classified as highly emetogenic chemotherapies (HEC) [7-10]. Adherence to the guidelines demonstrated a strong correlation with the improvement of CINV control in PEER or INSPIRE studies with significant reductions in CINV incidences [11,12].

However, the use of antiemetic drugs for CINV was still an issue. In high-income countries, where mostly antiemetic medications are available, overuse was reported in 24.1% of patients of various CINV risk groups [13], and in up to 70% of patients receiving low-emetogenic chemotherapies (LEC) [6]. No prophylaxis or a lack of prophylactic duration were also reported as the main reasons for non-adherence to the clinical guidelines in these countries [11,12]. In resource-limited countries, it’s more challenging to follow the antiemetic guidelines, as it is presumed that “socio-economic status” is one of the rationales for non-adherence [14]. A study in Jordan showed that there were no NK1RA in the CINV prophylaxis therapy, and the prevalence of CINV was as high as more than 70% in the included patients [15]. In a study based on medication data in China, there was also a lack of NK1RA and an overutilization of the other antiemetic agents [16]. Therefore, it’s essential to reveal prophylactic problems to improve the practice of CINV prophylaxis and patient outcomes. In Vietnam, a resource-limited country, antiemetic medications were not available in full range, and information about CINV prophylaxis and its effectiveness was limited. Therefore, we conducted this study to investigate the patterns of CINV prophylaxis in Vietnam and patient-reported CINV events to explore the potential gap in practice. With that, we expected to propose measurements to use the limited healthcare resources optimally and to improve patient outcomes in the future.

METHODS

Study Design, Settings and Patient Selection

This prospective, observational study was conducted at two oncology-specialized hospitals in North Vietnam from March 2019 to June 2019. Patients were eligible if they had a confirmed cancer diagnosis, were aged ≥18 years, and were scheduled to take the first cycle of a single-day, intravenous chemotherapy. The emetic risk of chemotherapy was classified as HEC, moderate emetogenic chemotherapy (MEC), and LEC according to the NCCN guidelines for anti-emesis version 2019.1 [17]. Patients who concurrently took (an) oral cytotoxic agent(s), used to be treated with chemotherapy, experienced nausea or vomiting in 24 hours before the administration of the chemotherapy, had brain metastases or bowel obstruction, or whose medical records were not accessed, were excluded.

Data Collection

Data collection consisted of medical record extraction and patient interviews. A form was created to retrieve data from medical records, which included patient demographic and clinical characteristics, the prescribed chemotherapy and medications for CINV prophylaxis, and other co-medications. The demographic and clinical characteristics consisted of age, gender, body weight and height, type of cancer, comorbidities, and the status of concurrent radiotherapy. The chemotherapy and all prescribed medications were recorded for their names and active ingredients, route of administration, dose, and duration. A questionnaire about risk factors for CINV, including history of balance disorder, motion sickness, nausea and vomiting related to pregnancy (if applicable), anxiety about chemotherapy, and frequency of alcohol drinking, was used to interview patients. The Multinational Association of Supportive Care in Cancer Antiemesis Tool (MAT), a validated tool to measure CINV, was used to assess patients’ experiences of the occurrence and severity of nausea and vomiting [18]. Permission to use MAT was granted by the Multinational Association of Supportive Care in Cancer (MASCC).

There was a pre-established process for data collection. Every day during the study period, the clinical pharmacists screened a list of patients admitted to the hospitals for those with the first cycle of chemotherapy. Their medical records were reviewed to select eligible patients for the study and to collect the data on the form. The selected patients were interviewed to obtain their risk factors for CINV and were introduced to MAT before or during their administration of chemotherapy. The time of the initiation of the chemotherapy administration was noted to identify the acute and delayed phases of CINV. The patients were approached twice, 24 hours and 120 hours after the chemotherapy, for their responses to MAT in the acute and delayed phases, respectively. The process is summarized in Fig. 1.

Figure 1. Patient recruitment flow.
MAT=The Multinational Association of Supportive Care in Cancer Antiemesis Tool.

Outcome Measure

The MAT used to evaluate patients’ experiences of nausea and vomiting consists of eight items. The first four are for nausea and vomiting for the acute phase, which is 24 hours following chemotherapy, and the last four items are for the delay phase, the period after that until 120 hours. In both phases, patients were asked whether they experienced nausea (items 3 and 7) and vomiting (items 1 and 5). They were asked about the severity of nausea (items 4 and 8) on a scale from 0 (no nausea) to 10 (as much as possible) and the number of vomiting episodes (items 2 and 6) [18]. In this study, the events of CINV were defined as severe if patients reported from four episodes of vomiting, or from level six of nausea in the questions about CINV severity in MAT.

Definition of Exposure

As for the 5-HT3RA, the upper limit of an agent’s daily dose recommended for the acute phase by NCCN [17], which were similar to those by ASCO, MASCC and ESMO [7-10], and was considered one recommended dose (RD). One RD of the locally available 5-HT3RA was 0.25 mg of intravenous (IV) palonosetron, 24 mg of oral ondansetron, 16 mg of IV ondansetron, or 1 mg of IV granisetron. If the 5-HT3RA daily dose of a patient was higher than one RD, it would be classified as a high dose of 5-HT3RA.

As the NCCN guidelines recommended that in prophylactic regimens with a NK1RA, the daily doses of dexamethasone are 12 mg and 8 mg for the acute and delayed phases, respectively, and higher glucocorticoid (GC) doses should be used when a NK1RA agent is not given concomitantly [17]. Therefore, the daily dose of GC was considered to be high if it was higher than 12 mg of dexamethasone for the acute phase and more than 8 mg of dexamethasone for the delayed phase. The GC included in the chemotherapy regimen was also calculated for the CINV prophylaxis.

The medications used on the day of CT were recorded for the acute phase (day 1), and those on the following days were for the delayed phase (from day 2 to day 4). Patients were considered to be covered by 5-HT3RA in the delayed phase if they were prescribed IV palonosetron on day 1 due to its long half-life [12].

Statistical Analyses

Patient demographic and clinical characteristics, risk factors were summarized using descriptive statistics. These factors, the pattern of prophylaxis, and the incidence of CINV were compared among groups of patients treated with HEC, MEC, and LEC using the Pearson Chi-square test or Fisher exact test for categorical variables and one way ANOVA for the continuous variables. The associations between demographics, clinical characteristics, risk factors, and the pattern of CINV prophylaxis were analyzed using χ2-test. The variable of emetic risks of CT but not cancer type was employed in the analysis because they are correlated, and the risk of CT was the primary criterion for CINV prophylactic regimen selection. The associations of the demographics and clinical characteristics, risk factors, the patterns of CINV prophylaxis with the occurrence of events in the acute and delayed phases were also examined using χ2-test. Then the factors that had the p-values less than 0.1 were included in the final logistic regression models (for bivariate outcome) or ordinal logistic regression model (for ordinal outcomes) to compute odds ratios and the corresponding 95% CI. The study was approved by Review board of Hanoi University of Pharmacy (Number 407/QD-DHN) and accepted by the study sites. Patients’ consents were obtained orally and by their agreement to join the interviews.

RESULTS

Demographic and Risk Factor Characteristics

The study included 294 patients in three groups: HEC, MEC, and LEC. The groups were significantly different in patients’ age, the frequent alcohol usage, the concomitant use of radiation therapy (RT), and the type of cancer (Table 1). The mean age was 54.4 years in the whole studied population, however, more patients under 60 years old were in the HEC group compared with MEC and LEC groups, 70.1% vs. 59.0% and 22.2% respectively (p=0.005). Patients treated with RT concurrently in HEC accounted for 33.0%, while it was 19.7% in MEC and 0% in LEC (p=0.02). In contrast, the proportion of patients with frequent use of alcohol was highest in the LEC group (55.6%) and they were quite similar in HEC and MEC groups (21.4% and 18.0%, respectively). Most of the patients had breast cancer (30.0%), digestive tract cancer (25.5%), or lung cancer (18.0%) of all patients. However, cancer diseases among the groups were significantly different (p<0.001).

Table 1 . Patient demographics and clinical characteristics.

Patient characteristics\NTotal (N=294)HEC (N=224)MEC
(N=61)
LEC
(N=9)
p-value
Age (year), mean (SD)54.4 (11.1)53.4 (10.7)56.6 (11.4)64.2 (13.7)0.003
Age <60 years old, n (%)195 (66.3)157 (70.1)36 (59.0)2 (22.2)0.005
BMI, n (%)0.13
<18.541 (13.9)29 (13.0)8 (13.1)4 (44.4)
18.5≤BMI<25226 (76.9)174 (77.7)48 (78.7)4 (44.4)
≥2527 (9.2)21 (9.4)5 (8.2)1 (11.1)
Female gender, n (%)171 (58.2)128 (57.1)39 (63.9)4 (44.4)0.44
Having comorbidity, n (%)100 (34.0)74 (33.0)23 (37.7)3 (33.3)0.79
Concurrent RT, n (%)86 (29.3)74 (33.0)12 (19.7)00.02
Nervousness before CT, n (%)15 (5.1)12 (5.4)3 (4.9)01.00
History of balance disorder, n (%)36 (12.2)31 (13.8)5 (8.2)00.26
History of carsick, n (%)103 (35.0)76 (33.9)26 (42.6)1 (11.1)0.14
History of nausea/vomit related to pregnancy, n (%)58 (19.7)42 (18.8)14 (23.0)2 (22.2)0.75
Frequent alcohol usage, n (%)64 (21.8)48 (21.4)11 (18.0)5 (55.6)0.04
Type of cancer, n (%)<0.0001
Breast cancer88 (30.0)61 (27.2)25 (41.0)2 (22.2)
Digestive tract cancer*75 (25.5)53 (23.7)22 (36.1)0
Lung cancer53 (18.0)44 (19.6)8 (13.1)1 (11.1)
Gynecologic cancer45 (15.3)41 (18.3)2 (3.3)2 (22.2)
Non-Hodgkin lymphoma17 (5.8)13 (5.8)4 (6.5)0
Others16 (5.4)12 (5.4)04 (44.5)

*Including tongue, nasopharyngeal, esophagus, gastric, colorectal cancer..

BMI=body mass index, CT=chemotherapy, HEC=high emetic risk chemotherapy, LEC=low emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, RT=radiotherapy, SD=standard deviation..



Patterns of CINV Prophylaxis

In the acute phase, a combination therapy of GC and 5-HT3RA was prescribed for all patients, regardless of the potential emetogenicity of the chemotherapy they used (Table 2). The proportions of patients treated with high doses of GC and 5-HT3RA were not significantly different among the groups (p=0.67 and 0.20, respectively). All patients with high doses of 5-HT3RA in this study used double the recommended doses.

Table 2 . Pattern of prophylaxis for chemotherapy induced-nausea and vomiting.

Pattern of CINV prophylaxis\NHEC (N=224)MEC (N=61)LEC (N=9)p-value
Acute phase - day 1
Prophylaxis therapy
GC+5HT3 RA224 (100.0)61 (100.0)9 (100.0)-
High dose of GC99 (44.2)24 (39.3)3 (33.3)0.67
High dose of 5-HT3 RA151 (67.4)34 (55.7)5 (55.6)0.20
Delayed phase - day 2
Prophylaxis therapy0.37
No use48 (21.4)14 (23.0)4 (44.4)
GC only23 (10.3)11 (18.0)1 (11.1)
5-HT3 RA only89 (39.7)19 (31.1)3 (33.3)
GC+5-HT3 RA64 (28.6)17 (27.9)1 (11.1)
High dose of GC11 (4.9)3 (4.9)0 (0)1.00
High dose of 5-HT3 RA29 (13.0)12 (19.7)1 (11.1)0.40
Delayed phase - day 3
Prophylaxis therapy0.10
No use124 (55.4)31 (50.8)8 (88.9)
GC only13 (5.8)6 (9.8)0 (0)
5-HT3 RA only70 (31.2)15 (24.6)0 (0)
GC+5-HT3 RA17 (7.6)9 (14.7)1 (11.1)
High dose of GC10 (4.5)1 (1.6)0 (0)0.62
High dose of 5-HT3 RA8 (3.6)7 (11.5)0 (0)0.06
Delayed phase - day 4
Prophylaxis therapy0.36
No use143 (63.8)45 (73.8)9 (100)
GC only9 (4.0)2 (3.3)0 (0)
5-HT3 RA only66 (29.5)13 (21.3)0 (0)
GC+5-HT3 RA6 (2.7)1 (1.6)0 (0)
High dose of GC8 (3.6)0 (0)0 (0)0.38
High dose of 5-HT3 RA3 (1.3)5 (8.2)0 (0)0.04

HEC=high emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, LEC=low emetic risk chemotherapy, GC=glucocorticoids, 5-HT3 RA=5-HT3 receptor antagonists..



In terms of prophylaxis for delayed nausea and vomiting, there was no statistically significant difference in the usage of anti-emesis medications for the patients in the groups from day 2 to day 4. The percentages of patients without prophylaxis increased from day 2 to day 4 (21.4%, 55.4% and 63.8% of the patients with HEC, respectively, and 23.0%, 50.8% and 73.8% of those with MEC, respectively). The proportion of the patients in HEC group treated with the combination of GC and 5-HT3RA was 28.6% on day 2 and decreased to 2.7% on day 4. Whereas 49.1% and 34.4% of the patients in MEC, were prophylactic with either GC or 5-HT3RA on day 2 and 3 respectively. The proportions of patients with high dose GC were under 5% across the groups of all the days.

Factors Associated with the Patterns of CINV Prophylaxis

The body mass index (BMI) equal or greater than 25 was the only factor related to the choice of high dose GC in the acute phase with OR=0.3 (0.10–0.87) compared to BMI less than 18.5 (Table 3). Fewer female than male patients were prescribed 5-HT3RA at the high dose in the acute phase (OR=0.42, 95% CI=0.02–0.87). However, the female patients were 2.47 times more likely to be treated enough or more days for the delayed prophylaxis than their male counterparts. They also tended to be treated with more drugs than men during the delayed phase, but were not significantly different. The patients having history of balance disorder were less likely to be treated enough or more days for the delayed prophylaxis (OR=0.4, 95% CI=0.17–0.91), while those with comorbidity were indicated two medications less frequent than the patients without comorbidity (OR=0.39, 95% CI=0.19–0.80).

Table 3 . Multi-variable analysis for factors associated with the pattern of CINV prophylaxis.

FactorsAcute phaseDelayed phase
High dose of GC*High dose of 5-HT3 RA*More or enough days of delayed prophylaxis*Number of drugs selection#
2 drugs
(5-HT3 RA and GC) vs. no use
1 drug
(5-HT3 RA or GC) vs. no use
Emetic risk of CT----
HEC0.64 (0.35-1.17)
MEC1
LECNE
Female gender (yes vs. no)-0.42 (0.20-0.87)2.47 (1.29-4.75)1.38 (0.64-2.98)1.92 (0.96-3.85)
Age <60 years old (yes vs. no)-0.57 (0.32-0.99)---
Concurrent RT (yes vs. no)-1.69 (0.92-3.10)1.03 (0.57-1.85)--
Nervousness before CT
(yes vs. no)
-----
History of balance disorder
(yes vs. no)
--0.40 (0.17-0.91)--
History of carsick (yes vs. no)-0.92 (0.51-1.64)1.25 (0.69-2.26)1.10 (0.47-2.59)1.35 (0.64-2.86)
History of nausea/vomit related to pregnancy (yes vs. no)--1.23 (0.63-2.40)--
Frequent alcohol usage
(yes vs. no)
-1.24 (0.53-2.93)---
Having comorbidity (yes vs. no)---0.39 (0.19-0.80)0.78 (0.42-1.43)
BMI----
<18.51
18.5≤BMI<250.65 (0.33-1.27)
≥250.30 (0.10-0.87)

Values are presented as odds ratio (95% confidence interval)..

*Multi-variable logistic regression model including variables with p<0.1 in univariate analysis, #multi-variable ordinal regression model including variables with p<0.1 in univariate analysis. -variables tested in univariate analysis that had p-values ≥0.1..

CINV=chemotherapy induced nausea and vomiting, OR=odds ratio, CI=confident interval, GC=glucocorticoids, 5-HT3 RA=5-HT3 receptor antagonists, CT=chemotherapy, HEC=high emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, LEC=low emetic risk chemotherapy, NE=not estimated due to no event in the group, RT=radiotherapy, BMI=body mass index..



CINV Incidence and its Associated Factors

CINV happened in 20.8% and 46.4% of the patients in the acute and delayed phase respectively, and 47.3% experienced CINV in either phase (Table 4). The incidence of nausea was higher than of vomiting in both phases, and the delayed events happened more frequently than the acute ones in all categories. When comparing amongst groups of emetic risk, the higher risk groups had the higher incidences of the events with significant difference in some types of events such as: all CINV (p=0.01), all delayed CINV (p=0.04) and severe delayed CINV (p=0.02) (Table 4).

Table 4 . CINV incidences and the comparison among emetogenic risk groups.

CINV\NTotal (n=294)HEC (n=224)MEC (n=61)LEC (n=9)p-value
All CINV139 (47.3)116 (51.8)22 (36.1)1 (11.1)0.01
All acute CINV61 (20.8)53 (23.7)8 (13.1)00.06
Acute vomiting29 (9.9)25 (11.2)4 (6.6)00.34
Acute nausea60 (20.4)52 (23.2)8 (13.1)00.07
Severe acute CINV31 (10.5)27 (12.1)4 (6.6)00.27
Severe acute vomiting18 (6.1)16 (7.1)2 (3.3)00.65
Severe acute nausea28 (9.5)25 (11.2)3 (4.9)00.21
All delayed CINV#131 (46.4)108 (50.0)22 (37.9)1 (12.5)0.04
Delayed vomiting72 (25.5)62 (28.7)10 (17.2)00.05
Delayed nausea125 (44.3)103 (47.7)21 (36.2)1 (12.5)0.06
Severe delayed CINV#69 (23.5)61 (28.2)8 (13.8)00.02
Severe delayed vomiting35 (12.4)30 (13.9)5 (8.6)00.31
Severe delayed nausea57 (20.2)50 (23.2)7 (12.1)00.06

#There were 282, 216, 61 and 8 patients in total, HEC, MEC and LEC group respectively because some patients were lost to contact in the delayed phase..

CINV=chemotherapy induced nausea and vomiting, HEC=high emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, LEC=low emetic risk chemotherapy..



The multiple logistic regression analysis showed that patients treated with HEC was the only factor related to the 2.34 times higher risk of developing acute CINV than with MEC (OR=2.34 95% CI=1.03–5.32). Whereas HEC also tended to have more delayed CINV but non-significantly after controlling other factors. Female gender was associated with higher risk of acute and delayed CINV but only statistically significant in two models of delayed CINV (Table 5). For the risk of delayed CINV, in the model 1, besides gender, the occurrence of acute CINV increased the risk of delayed events by 10.26 times (95% CI=4.45–23.63). In the model 2, which excluded the patients with acute CINV, younger age was an additional factor associated with the increased risk of the event by 2.08 times (95% CI=1.07–4.07) after controlling for the others.

Table 5 . Multivariate logistic regression analysis for acute and delayed CINV.

Factors\NAcute CINV* (N=294)Delayed CINV
Model 1*,# (N=282)Model 2*,$ (N=221)
Emetic risk of CT
HEC2.34 (1.03-5.32)1.47 (0.74-2.90)1.87 (0.88-3.96)
MEC111
LECNE0.44 (0.05-4.27)0.45 (0.04-4.83)
Female gender (yes vs. no)1.95 (0.902-4.21)3.22 (1.41-7.33)3.38 (1.38-8.28)
Age <60 years old (yes vs. no)-1.76 (0.96-3.22)2.08 (1.07-4.07)
Concurrent RT (yes vs. no)---
Nervousness before CT (yes vs. no)---
History of balance disorder (yes vs. no)---
History of carsick (yes vs. no)1.57 (0.80-3.10)1.18 (0.61-2.29)1.19 (0.58-2.44)
History of nausea/vomiting related to pregnancy (yes vs. no)1.34 (0.65-2.76)1.36 (0.64-2.91)1.97 (0.86-4.54)
Frequent alcohol usage (yes vs. no)-1.56 (0.65-3.73)1.32 (0.50-3.52)
Having comorbidity (yes vs. no)---
BMI (18.5≤ BMI<25, ≥25 vs. <18)---
High dose of acute GC (yes vs. no)---
High dose of 5-HT3RAs in the acute phase (yes vs. no)---
Days of delayed CINV prophylaxisNT--
Therapy selectionNT--
No used1-
1 drug1.74 (0.78-3.88)1.41 (0.60-3.33)
2 drugs1.17 (0.56-2.44)0.85 (0.38-1.88)
Occurrence of acute CINVNT10.26 (4.45-23.63)NT

Values are presented as odds ratio (95% confidence interval)..

*Multi-variable logistic regression model including variables with p<0.1 in univariate analysis, #Model included all patients with available information for delayed CINV (N=282), $Model excluded patients with acute CINV (N=221), -variables tested in univariate analysis that had p-values ≥0.1..

CINV=chemotherapy induced nausea and vomiting, OR=odds ratio, CI=confident interval, CT=chemotherapy, HEC=high emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, LEC=low emetic risk chemotherapy, NE=not estimated due to no event in the group. RT=radiotherapy, BMI=body mass index, GC=glucocorticoids, 5-HT3 RA=5-HT3 receptor antagonists, NT=not tested in univariate and multivariate analysis..


DISCUSSION

Although there were international and local emetic prophylaxis guidelines for patients receiving chemotherapy, we could not evaluate the adherence to these because of the lack of preventive medications (NK1RA) and the non-updated local guidelines [19]. However, this study revealed that the prophylactic patterns had the potential for both overuse and underuse. Underuse, i.e., lack of medication or insufficient doses according to the recommendations of the clinical guidelines, such as the ASCO, NCCN, and MASCC and ESMO guidelines for CINV prevention and treatment, may result in suboptimal patient outcomes, specifically nausea and vomiting, which occurred in approximately half of the included patients in the current study. Overuse, or the use of a medication not recommended by the guidelines mentioned above or at a higher dose than the recommended one, may lead to adverse effects and a waste of resources that could be allocated to better choices.

The patients in the HEC group were supposed to have more aggressive treatment. However, the prophylaxis patterns of the group did not differ from the other two groups MEC and LEC (Table 2), and the emetic risks of CT were not associated with physicians’ decisions about the anti-emesis drug selection, doses and durations of treatment (Table 3). Even patients in the HEC group seemed to have more other risk factors for nausea and vomiting such as concurrently treated with RT, younger age, and without the habit of consuming alcohol frequently [20,21].These results demonstrated a potential for improper CINV prophylaxis in the study.

Due to the unavailability of NK1RA in Vietnam, the prophylaxis for patients treated with HEC might be more likely to be insufficient. Olanzapine, which could be a choice according to the international guidelines, was not used in the study. A higher dose of GC, which was recommended in case of no NK1RA [9,17], was prescribed in 44.2% of the patients in the acute phase and in less than 5% in the delayed phase. The lack of prophylaxis for the delayed phase could also be seen in patients with no prevention medication in HEC group (21.4% on day 2, 55.4% on day 3 and 63.8% on day 4) and MEC groups (23.0% and 50.8% on day 2 and 3, respectively), or low proportion of patients in HEC having combination therapy.

Olanzapine was not utilized, which could be due to its weak evidence and the fear of its side effects such as QT prolongation (especially when combined with a 5-HT3RA). Moreover, olanzapine was not yet in the local guideline for CINV prophylaxis and it did not have the indication in the label. As a result, it was not covered by insurance, which could be a barrier to the usage. However, olanzapine did not cost much for several days and could be an acceptable solution for several specific patients receiving HEC. Ideally, the local guideline should be updated with taking olanzapine into consideration.

Another resolution for the lack of NK1RA was a higher dose of GC. However, HEC was not shown to relate with the choice of high dose GC in this study. The median dose of GC in the patients with high dose was still low (16 mg, IQR: 16–20 mg) for the acute phase, comparing with the recommendation of 20 mg in the local or ESMO guideline in the absence of NK1RA [9,19]. Therefore, high dose GC in this study did not show relation to the patients’ outcomes. This practice still gave a room to improve the clinical outcomes by using a higher dose of GC for patients with HEC.

In contrast, there was still a potential overuse of prophylactic medications. It was seen in the use of combination therapy in 100% of patients with LEC on day 1, and in 27.9% and 14.7% of patients with MEC on days 2 and 3, respectively, where a single drug of GC or a 5-HT3RA is recommended. The use of a high dose of 5-HT3RAs for the acute phase in 55.6% to 67.4% of patients in all groups was also a source of wasting. The high doses of 5-HT3RAs in this study were almost double those in the international guidelines. Although these guidelines are similar for 5-HT3RA dose recommendations [9,17], the local guidelines do not provide guidance on the doses, which could be a difficulty for physicians [19]. The prices for one-day treatment of these medications are usually 5–10 times higher than those of GC or olanzapine, according to the prices on the website of Drug Administration of Vietnam [22]. A high dose of 5-HT3RA also did not relate to the decrease in CINV occurrence in this study. Therefore, to save resources, the selection or dose of 5-HT3RA should be considered carefully.

In the current study, gender was a factor related to many aspects of CINV prophylaxis therapy, which could be understandable. Female patients, who are associated with a higher risk of CINV occurrence [20,21], were more likely to be treated with more drugs or for a longer duration in the delayed phase than their male counterparts. However, they were less likely to be prescribed high doses of 5-HT3RA, which could be explained by the fact that physicians may be more careful with the adverse effects of 5-HT3RA such as QT prolongation and torsade point, which are more likely to happen in women. In contrast, the potential emetogenicity of CT, which is usually the basis for choosing the therapy in the evidence guidelines, was not shown to be associated with the CINV prophylaxis patterns. Besides, patients with other risk factors for CINV, including younger age and a history of balance disorder [20,21], were chosen for less intensive therapy in the current study. These findings supported the aforementioned results that no difference in the prophylactic patterns among the LEC, MEC, and HEC groups was seen.

The incidences of different types of CINV showed the higher proportions in the higher emetic risk groups with significant differences (for all CINV: p=0.01, delayed CINV: p=0.04 or severe delayed CINV: p=0.02). This is understandable due to the similar patterns of prophylaxis among the three groups. Results from the regression analysis also confirmed these findings by showing the increased risk of developing CINV in HEC group in both the acute and delayed phase after controlling for other factors, although it did not show significantly different in the delayed phase. In the model 1 of the delayed phase, experiences of CINV in the acute phase increased the risk of delayed event by 10.26 times, which also meant an indirect relation of HEC to the delayed events. From these results, we raise the importance of following the practice guidelines, which are all based majorly on the emetic risk of CT.

Beside the emetic risk of CT, from multivariable logistic regression analysis, we found female gender and younger age were associated with both acute and delayed events. These findings were consistent with previous studies [20,23,24]. Recently, the prediction models of CINV risk have been developed taking into account patients’ factors for appropriate choices of antiemetics [25,26].

About the incidence of CINV, it was 47.3% in the current study, meaning that 52.7% patients did not experience any CINV. This rate was lower than that reported in a study conducted in 6 Asia Pacific countries in 2014 of which the complete response rate was 69% [27]. However, it was similar to the findings of a study in 8 European countries in 2010 which showed that the proportion of no CINV in the first cycle were 50.7% and 59.9% in the groups of non-adherence and adherence to anti emesis guidelines respectively [11]. At that time NK1RA and olanzapine had not yet been recommended in the ESMO guideline [10].

When looking at nausea and vomiting separately, the incidences of nausea were higher in both acute and delayed phases in the current study, 20.4% vs. 9.9% and 42.5% vs. 24.5% respectively, which showed that nausea was more difficult to control than vomiting. These patterns were similar to those in the recent studies in Korea and Jordan. In the Korean study, the rates of nausea in the acute and delayed phases were much higher than ours (46% and 83% respectively), while those of acute and delayed vomiting were quite similar (8.3% and 23%, respectively) [28]. However, the patients in that study received HEC and MEC only. In Jordan where NK1RA and olanzapine were not prescribed in the prophylaxis like the practice in ours, nausea and vomiting were at higher rates, about 60% and 42% respectively in acute phase, and similarly in the delayed phase [15].

Although this current study revealed the situation of CINV prophylaxis and patients’ outcomes, it had some limitations to be acknowledged. First, it only recorded the prescribed preventive medications for the patients to use at the hospitals and to take home after their CT administration. During the delayed phase at home, whether they took the medication and whether their medication were changed due to the occurrence of CINV were not studied. Therefore, it might interfere the effects of the prophylaxis regimens on CINV occurrence and severity. However, the description of the patterns of CINV prophylaxis still reflected the reality of the current practice, which was the main objective of this study. Second, the disparity in the number of patients among groups of CINV risks (HEC, MEC, and LEC) and their characteristics could affect the comparisons among the groups. This limitation is due to the nature of the cross-sectional study design used in this study, which is not allowed to allocate or match patients among groups. Third, this study did not consider physicians’ prescribing behaviors, which could also contribute to the pattern of CINV prophylaxis, especially the overuse in LEC and MEC groups and the underuse in HEC. Future research, including physician interviews about their prescribing behaviors, is needed to explore underlying reasons.

In conclusion, the pattern of CINV prophylaxis in this study showed a potential over- and under-use of anti-emesis medication. Emetic risk of CT has not yet been a key factor to consider a pattern of CINV prophylaxis, and CT with higher emetic risk was associated with higher possibility of developing CINV. While the resource was limited, more effort should be made to allocate the current resources effectively by taking into account the aspects recommended in the reputed guidelines such as emetic risk of CT and doses of medications. Ideally, an up-to-date local guideline should be established based on local resources, the available data and the international evidence-based guidelines to standardize the practice.

CONCLUSION

In conclusion, the pattern of CINV prophylaxis in this study showed a potential over- and under-use of anti-emesis medication. Emetic risk of CT has not yet been a key factor to consider a pattern of CINV prophylaxis, and CT with higher emetic risk was associated with higher possibility of developing CINV. While the resource was limited, more effort should be made to allocate the current resources effectively by taking into account the aspects recommended in the reputed guidelines such as emetic risk of CT and doses of medications. Ideally, an up-to-date local guideline should be established based on local resources, the available data and the international evidence-based guidelines to standardize the practice.

FUNDING

None.

ACKNOWLEDGMENTS

We would like to thank the participants who generously agreed to participate in the study and the pharmacy students who facilitated recruitment to this study. We also appreciate the thorough support of the participant hospitals, which allowed us to collect sufficient data for this study.

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

Fig 1.

Figure 1.Patient recruitment flow.
MAT=The Multinational Association of Supportive Care in Cancer Antiemesis Tool.
Researh in Clinical Pharmacy 2023; 1: 115-126https://doi.org/10.59931/rcp.23.030

Table 1 Patient demographics and clinical characteristics

Patient characteristics\NTotal (N=294)HEC (N=224)MEC
(N=61)
LEC
(N=9)
p-value
Age (year), mean (SD)54.4 (11.1)53.4 (10.7)56.6 (11.4)64.2 (13.7)0.003
Age <60 years old, n (%)195 (66.3)157 (70.1)36 (59.0)2 (22.2)0.005
BMI, n (%)0.13
<18.541 (13.9)29 (13.0)8 (13.1)4 (44.4)
18.5≤BMI<25226 (76.9)174 (77.7)48 (78.7)4 (44.4)
≥2527 (9.2)21 (9.4)5 (8.2)1 (11.1)
Female gender, n (%)171 (58.2)128 (57.1)39 (63.9)4 (44.4)0.44
Having comorbidity, n (%)100 (34.0)74 (33.0)23 (37.7)3 (33.3)0.79
Concurrent RT, n (%)86 (29.3)74 (33.0)12 (19.7)00.02
Nervousness before CT, n (%)15 (5.1)12 (5.4)3 (4.9)01.00
History of balance disorder, n (%)36 (12.2)31 (13.8)5 (8.2)00.26
History of carsick, n (%)103 (35.0)76 (33.9)26 (42.6)1 (11.1)0.14
History of nausea/vomit related to pregnancy, n (%)58 (19.7)42 (18.8)14 (23.0)2 (22.2)0.75
Frequent alcohol usage, n (%)64 (21.8)48 (21.4)11 (18.0)5 (55.6)0.04
Type of cancer, n (%)<0.0001
Breast cancer88 (30.0)61 (27.2)25 (41.0)2 (22.2)
Digestive tract cancer*75 (25.5)53 (23.7)22 (36.1)0
Lung cancer53 (18.0)44 (19.6)8 (13.1)1 (11.1)
Gynecologic cancer45 (15.3)41 (18.3)2 (3.3)2 (22.2)
Non-Hodgkin lymphoma17 (5.8)13 (5.8)4 (6.5)0
Others16 (5.4)12 (5.4)04 (44.5)

*Including tongue, nasopharyngeal, esophagus, gastric, colorectal cancer.

BMI=body mass index, CT=chemotherapy, HEC=high emetic risk chemotherapy, LEC=low emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, RT=radiotherapy, SD=standard deviation.


Table 2 Pattern of prophylaxis for chemotherapy induced-nausea and vomiting

Pattern of CINV prophylaxis\NHEC (N=224)MEC (N=61)LEC (N=9)p-value
Acute phase - day 1
Prophylaxis therapy
GC+5HT3 RA224 (100.0)61 (100.0)9 (100.0)-
High dose of GC99 (44.2)24 (39.3)3 (33.3)0.67
High dose of 5-HT3 RA151 (67.4)34 (55.7)5 (55.6)0.20
Delayed phase - day 2
Prophylaxis therapy0.37
No use48 (21.4)14 (23.0)4 (44.4)
GC only23 (10.3)11 (18.0)1 (11.1)
5-HT3 RA only89 (39.7)19 (31.1)3 (33.3)
GC+5-HT3 RA64 (28.6)17 (27.9)1 (11.1)
High dose of GC11 (4.9)3 (4.9)0 (0)1.00
High dose of 5-HT3 RA29 (13.0)12 (19.7)1 (11.1)0.40
Delayed phase - day 3
Prophylaxis therapy0.10
No use124 (55.4)31 (50.8)8 (88.9)
GC only13 (5.8)6 (9.8)0 (0)
5-HT3 RA only70 (31.2)15 (24.6)0 (0)
GC+5-HT3 RA17 (7.6)9 (14.7)1 (11.1)
High dose of GC10 (4.5)1 (1.6)0 (0)0.62
High dose of 5-HT3 RA8 (3.6)7 (11.5)0 (0)0.06
Delayed phase - day 4
Prophylaxis therapy0.36
No use143 (63.8)45 (73.8)9 (100)
GC only9 (4.0)2 (3.3)0 (0)
5-HT3 RA only66 (29.5)13 (21.3)0 (0)
GC+5-HT3 RA6 (2.7)1 (1.6)0 (0)
High dose of GC8 (3.6)0 (0)0 (0)0.38
High dose of 5-HT3 RA3 (1.3)5 (8.2)0 (0)0.04

HEC=high emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, LEC=low emetic risk chemotherapy, GC=glucocorticoids, 5-HT3 RA=5-HT3 receptor antagonists.


Table 3 Multi-variable analysis for factors associated with the pattern of CINV prophylaxis

FactorsAcute phaseDelayed phase
High dose of GC*High dose of 5-HT3 RA*More or enough days of delayed prophylaxis*Number of drugs selection#
2 drugs
(5-HT3 RA and GC) vs. no use
1 drug
(5-HT3 RA or GC) vs. no use
Emetic risk of CT----
HEC0.64 (0.35-1.17)
MEC1
LECNE
Female gender (yes vs. no)-0.42 (0.20-0.87)2.47 (1.29-4.75)1.38 (0.64-2.98)1.92 (0.96-3.85)
Age <60 years old (yes vs. no)-0.57 (0.32-0.99)---
Concurrent RT (yes vs. no)-1.69 (0.92-3.10)1.03 (0.57-1.85)--
Nervousness before CT
(yes vs. no)
-----
History of balance disorder
(yes vs. no)
--0.40 (0.17-0.91)--
History of carsick (yes vs. no)-0.92 (0.51-1.64)1.25 (0.69-2.26)1.10 (0.47-2.59)1.35 (0.64-2.86)
History of nausea/vomit related to pregnancy (yes vs. no)--1.23 (0.63-2.40)--
Frequent alcohol usage
(yes vs. no)
-1.24 (0.53-2.93)---
Having comorbidity (yes vs. no)---0.39 (0.19-0.80)0.78 (0.42-1.43)
BMI----
<18.51
18.5≤BMI<250.65 (0.33-1.27)
≥250.30 (0.10-0.87)

Values are presented as odds ratio (95% confidence interval).

*Multi-variable logistic regression model including variables with p<0.1 in univariate analysis, #multi-variable ordinal regression model including variables with p<0.1 in univariate analysis. -variables tested in univariate analysis that had p-values ≥0.1.

CINV=chemotherapy induced nausea and vomiting, OR=odds ratio, CI=confident interval, GC=glucocorticoids, 5-HT3 RA=5-HT3 receptor antagonists, CT=chemotherapy, HEC=high emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, LEC=low emetic risk chemotherapy, NE=not estimated due to no event in the group, RT=radiotherapy, BMI=body mass index.


Table 4 CINV incidences and the comparison among emetogenic risk groups

CINV\NTotal (n=294)HEC (n=224)MEC (n=61)LEC (n=9)p-value
All CINV139 (47.3)116 (51.8)22 (36.1)1 (11.1)0.01
All acute CINV61 (20.8)53 (23.7)8 (13.1)00.06
Acute vomiting29 (9.9)25 (11.2)4 (6.6)00.34
Acute nausea60 (20.4)52 (23.2)8 (13.1)00.07
Severe acute CINV31 (10.5)27 (12.1)4 (6.6)00.27
Severe acute vomiting18 (6.1)16 (7.1)2 (3.3)00.65
Severe acute nausea28 (9.5)25 (11.2)3 (4.9)00.21
All delayed CINV#131 (46.4)108 (50.0)22 (37.9)1 (12.5)0.04
Delayed vomiting72 (25.5)62 (28.7)10 (17.2)00.05
Delayed nausea125 (44.3)103 (47.7)21 (36.2)1 (12.5)0.06
Severe delayed CINV#69 (23.5)61 (28.2)8 (13.8)00.02
Severe delayed vomiting35 (12.4)30 (13.9)5 (8.6)00.31
Severe delayed nausea57 (20.2)50 (23.2)7 (12.1)00.06

#There were 282, 216, 61 and 8 patients in total, HEC, MEC and LEC group respectively because some patients were lost to contact in the delayed phase.

CINV=chemotherapy induced nausea and vomiting, HEC=high emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, LEC=low emetic risk chemotherapy.


Table 5 Multivariate logistic regression analysis for acute and delayed CINV

Factors\NAcute CINV* (N=294)Delayed CINV
Model 1*,# (N=282)Model 2*,$ (N=221)
Emetic risk of CT
HEC2.34 (1.03-5.32)1.47 (0.74-2.90)1.87 (0.88-3.96)
MEC111
LECNE0.44 (0.05-4.27)0.45 (0.04-4.83)
Female gender (yes vs. no)1.95 (0.902-4.21)3.22 (1.41-7.33)3.38 (1.38-8.28)
Age <60 years old (yes vs. no)-1.76 (0.96-3.22)2.08 (1.07-4.07)
Concurrent RT (yes vs. no)---
Nervousness before CT (yes vs. no)---
History of balance disorder (yes vs. no)---
History of carsick (yes vs. no)1.57 (0.80-3.10)1.18 (0.61-2.29)1.19 (0.58-2.44)
History of nausea/vomiting related to pregnancy (yes vs. no)1.34 (0.65-2.76)1.36 (0.64-2.91)1.97 (0.86-4.54)
Frequent alcohol usage (yes vs. no)-1.56 (0.65-3.73)1.32 (0.50-3.52)
Having comorbidity (yes vs. no)---
BMI (18.5≤ BMI<25, ≥25 vs. <18)---
High dose of acute GC (yes vs. no)---
High dose of 5-HT3RAs in the acute phase (yes vs. no)---
Days of delayed CINV prophylaxisNT--
Therapy selectionNT--
No used1-
1 drug1.74 (0.78-3.88)1.41 (0.60-3.33)
2 drugs1.17 (0.56-2.44)0.85 (0.38-1.88)
Occurrence of acute CINVNT10.26 (4.45-23.63)NT

Values are presented as odds ratio (95% confidence interval).

*Multi-variable logistic regression model including variables with p<0.1 in univariate analysis, #Model included all patients with available information for delayed CINV (N=282), $Model excluded patients with acute CINV (N=221), -variables tested in univariate analysis that had p-values ≥0.1.

CINV=chemotherapy induced nausea and vomiting, OR=odds ratio, CI=confident interval, CT=chemotherapy, HEC=high emetic risk chemotherapy, MEC=moderate emetic risk chemotherapy, LEC=low emetic risk chemotherapy, NE=not estimated due to no event in the group. RT=radiotherapy, BMI=body mass index, GC=glucocorticoids, 5-HT3 RA=5-HT3 receptor antagonists, NT=not tested in univariate and multivariate analysis.


References

  1. de Boer-Dennert M, de Wit R, Schmitz PI, et al. Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer 1997; 76(8):1055-61.
    Pubmed KoreaMed CrossRef
  2. Cohen L, de Moor CA, Eisenberg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007 May; 15(5):497-503.
    Pubmed CrossRef
  3. Bloechl-Daum B, Deuson RR, Mavros P, Hansen M, Herrstedt J. Delayed nausea and vomiting continue to reduce patients' quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment. J Clin Oncol. 2006 Sep 20; 24(27):4472-8.
    Pubmed CrossRef
  4. Schwartzberg L, Harrow B, Lal LS, Radtchenko J, Lyman GH. Resource utilization for chemotherapy-induced nausea and vomiting events in patients with solid tumors treated with antiemetic regimens. Am Health Drug Benefits. 2015 Jul-Aug; 8(5):273-82.
  5. Schnell FM. Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. Oncologist 2003; 8(2):187-98.
    Pubmed CrossRef
  6. Schleicher SM, Bach PB, Matsoukas K, Korenstein D. Medication overuse in oncology: current trends and future implications for patients and society. Lancet Oncol. 2018 Apr; 19(4):e200-8.
    Pubmed CrossRef
  7. Razvi Y, Chan S, McFarlane T, et al. ASCO, NCCN, MASCC/ESMO: a comparison of antiemetic guidelines for the treatment of chemotherapy-induced nausea and vomiting in adult patients. Support Care Cancer. 2019 Jan; 27(1):87-95.
    Pubmed CrossRef
  8. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2017 Oct 1; 35(28):3240-61.
    Pubmed CrossRef
  9. Roila F, Molassiotis A, Herrstedt J, et al; participants of the MASCC/ESMO Consensus Conference Copenhagen 2015. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol. 2016 Sep; 27(Suppl 5):v119-33.
    Pubmed CrossRef
  10. Navari RM, Aapro M. Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med. 2016 Apr 7; 374(14):1356-67.
    Pubmed CrossRef
  11. Aapro M, Molassiotis A, Dicato M, et al; PEER Investigators. The effect of guideline-consistent antiemetic therapy on chemotherapy-induced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol. 2012 Aug; 23(8):1986-92.
    Pubmed CrossRef
  12. Gilmore JW, Peacock NW, Gu A, et al. Antiemetic guideline consistency and incidence of chemotherapy-induced nausea and vomiting in US community oncology practice: INSPIRE Study. J Oncol Pract. 2014 Jan; 10(1):68-74.
    Pubmed CrossRef
  13. Encinosa W, Davidoff AJ. Changes in antiemetic overuse in response to choosing wisely recommendations. JAMA Oncol. 2017 Mar 1; 3(3):320-6.
    Pubmed CrossRef
  14. Andreae MH, Gabry JS, Goodrich B, White RS, Hall C. Antiemetic prophylaxis as a marker of health care disparities in the National Anesthesia Clinical Outcomes Registry. Anesth Analg. 2018 Feb; 126(2):588-99.
    Pubmed KoreaMed CrossRef
  15. Al Qadire M. Chemotherapy-induced nausea and vomiting: incidence and management in Jordan. Clin Nurs Res. 2018 Jul; 27(6):730-42.
    Pubmed CrossRef
  16. Zong X, Zhang J, Ji X, Gao J, Ji J. Patterns of antiemetic prophylaxis for chemotherapy-induced nausea and vomiting in China. Chin J Cancer Res. 2016 Apr; 28(2):168-79.
    Pubmed KoreaMed CrossRef
  17. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology (2019) antiemetics. Version 1 [Internet]. Plymouth Meeting, PA: NCCN [cited 2019 Feb 28]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf
  18. Molassiotis A, Coventry PA, Stricker CT, et al. Validation and psychometric assessment of a short clinical scale to measure chemotherapy-induced nausea and vomiting: the MASCC antiemesis tool. J Pain Symptom Manage. 2007 Aug; 34(2):148-59.
    Pubmed CrossRef
  19. Ministry of Health. Technical process of specialized medical examination and treatment in oncology.
  20. Sekine I, Segawa Y, Kubota K, Saeki T. Risk factors of chemotherapy-induced nausea and vomiting: index for personalized antiemetic prophylaxis. Cancer Sci. 2013 Jun; 104(6):711-7.
    Pubmed KoreaMed CrossRef
  21. Mosa ASM, Hossain AM, Lavoie BJ, Yoo I. Patient-related risk factors for chemotherapy-induced nausea and vomiting: a systematic review. Front Pharmacol. 2020 Apr 1; 11:329.
    Pubmed KoreaMed CrossRef
  22. Drug Administration of Vietnam. Drug bank [Internet]. Hanoi: Ministry of Health [cited 2023 Sep 19]. Available from: https://drugbank.vn/tim-kiem?search=ondansetron&entity=tenThuoc&page=1&size=12
  23. Tamura K, Aiba K, Saeki T, et al; CINV Study Group of Japan. Testing the effectiveness of antiemetic guidelines: results of a prospective registry by the CINV Study Group of Japan. Int J Clin Oncol. 2015 Oct; 20(5):855-65.
    Pubmed CrossRef
  24. Tsuji D, Suzuki K, Kawasaki Y, et al. Risk factors associated with chemotherapy-induced nausea and vomiting in the triplet antiemetic regimen including palonosetron or granisetron for cisplatin-based chemotherapy: analysis of a randomized, double-blind controlled trial. Support Care Cancer. 2019 Mar; 27(3):1139-47.
    Pubmed CrossRef
  25. Molassiotis A, Stamataki Z, Kontopantelis E. Development and preliminary validation of a risk prediction model for chemotherapy-related nausea and vomiting. Support Care Cancer. 2013 Oct; 21(10):2759-67.
    Pubmed CrossRef
  26. Dranitsaris G, Molassiotis A, Clemons M, et al. The development of a prediction tool to identify cancer patients at high risk for chemotherapy-induced nausea and vomiting. Ann Oncol. 2017 Jun 1; 28(6):1260-7.
    Pubmed KoreaMed CrossRef
  27. Hsieh RK, Chan A, Kim HK, et al. Baseline patient characteristics, incidence of CINV, and physician perception of CINV incidence following moderately and highly emetogenic chemotherapy in Asia Pacific countries. Support Care Cancer. 2015 Jan; 23(1):263-72.
    Pubmed CrossRef
  28. Rha SY, Park Y, Song SK, Lee CE, Lee J. Controlling chemotherapy-induced nausea requires further improvement: symptom experience and risk factors among Korean patients. Support Care Cancer. 2016 Aug; 24(8):3379-89.
    Pubmed CrossRef
Asian Conference On Clinical Pharmacy

Vol.1 No.2
December 2023

eISSN 2983-0745
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