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Acute and delayed nausea and emesis control in pediatric oncology patients
Article first published online: 10 JAN 2006
Copyright © 2006 American Cancer Society
Volume 106, Issue 4, pages 931–940, 15 February 2006
How to Cite
Holdsworth, M. T., Raisch, D. W. and Frost, J. (2006), Acute and delayed nausea and emesis control in pediatric oncology patients. Cancer, 106: 931–940. doi: 10.1002/cncr.21631
- Issue published online: 3 FEB 2006
- Article first published online: 10 JAN 2006
- Manuscript Accepted: 23 AUG 2005
- Manuscript Revised: 19 AUG 2005
- Manuscript Received: 15 MAR 2005
To the authors' knowledge there is little information available regarding the effectiveness of standard antiemetic therapy among cancer patients who receive emetogenic chemotherapy in clinical practice, especially in the pediatric population. The current study was undertaken to determine the effectiveness of standard antiemetic interventions among children receiving emetogenic chemotherapy.
The authors conducted a retrospective review of antiemetic surveys for children who received emetogenic chemotherapy. Patients and/or their parents were surveyed for acute and delayed nausea and emesis after each course of emetogenic chemotherapy. The survey consisted of validated measures of the severity of nausea and emesis. Complete protection (CP) rates were calculated for each chemotherapy regimen during both the acute and delayed phases and also by gender and age group (ages birth–3 yrs, 4–11 yrs, and 12–20 yrs). Antiemetic therapy consisted of intravenous ondansetron administered once daily during chemotherapy either alone (for moderately emetogenic chemotherapy) or in combination with dexamethasone (for severely emetogenic chemotherapy).
In total, 224 different patients completed 1256 surveys. CP from both acute and delayed nausea and emesis was more likely in the children ages birth–3 years than in older children. For moderately emetogenic regimens, nausea and emesis in the acute and delayed phases were controlled well. Among severely emetogenic chemotherapy regimens, 7 of 12 different regimen types had CP rates < 50% in either the acute phase or the delayed phase. CP rates were particularly low for cisplatin-based and cyclophosphamide-based regimens.
Nausea and emesis remain significant problems among children who receive emetogenic chemotherapy. CP rates were associated significantly with patient age, and higher rates were observed among very young children. Cancer 2006. © 2006 American Cancer Society.
In adults, nausea and emesis remain the first and third most distressing chemotherapy side effects, respectively, despite the advent of modern antiemetic agents (e.g., 5-hydroxytryptamine-3 [5-HT3] antagonists).1 Most antiemetic studies have been performed in the adult population and have focused on the evaluation of new antiemetic agents. To our knowledge, little research has focused on the effectiveness in clinical practice of recommended antiemetic therapy for patients who are receiving chemotherapy, especially in the pediatric population. A few recent studies have documented the occurrence of nausea and emesis on the days of chemotherapy administration (acute phase) in children who were receiving certain chemotherapy regimens despite standard antiemetic medications.2, 3 However, little information currently is available in children regarding the degree of nausea and emesis that occurs in the days after chemotherapy is completed (delayed phase). Studies in the adult population indicate that nausea and emesis may be more severe when they are delayed than when they occur acutely, because delayed nausea and emesis are less responsive to standard antiemetic therapy.4–9 To our knowledge, only one study has characterized the occurrence and severity of delayed nausea and emesis in children who were receiving chemotherapy.10 The objective of the current study was to document the extent of nausea and emesis, despite appropriate antiemetic therapy, in both the acute phase and the delayed phase among children who were receiving various types of emetogenic chemotherapy. Specification of the degree of nausea and emesis associated with distinct types of chemotherapy in the acute and delayed phases may help clinicians target strategies for specific chemotherapy regimens.
MATERIALS AND METHODS
The current study was performed at a pediatric oncology clinic within a tertiary care hospital. The clinic is the only such entity in the state that provides comprehensive care for children with cancer.
According to standard care, all children with cancer who were receiving emetogenic chemotherapy that necessitated prophylaxis with an antiemetic were surveyed after the completion of chemotherapy. We obtained local Institution Review Board approval prior to collecting and analyzing these data. Once a data base was constructed, patient identifiers were removed to protect confidentiality. Because this research involved retrospective analysis of data collected for clinical purposes, a waiver of informed consent was granted.
The nausea/emesis survey consisted of a previously validated instrument with questions on nausea severity (NSEV) and duration, emesis (vomiting) severity (VSEV), the number of emesis episodes, interference with daily activities (DAI) by the nausea or emesis, and assessment of appetite.11 Construct validity of the survey was demonstrated by the high correlations between the following survey variables: NSEV, VSEV, DAI, and emesis episodes. In addition, the relatively low correlations between VSEV and nausea duration demonstrated content validity.11 NSEV, VSEV, and DAI each were scored on a 4 point Likert scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe). Appetite also was rated on a 4 point scale (0 = none, 1 = a little, 2 = some, and 3 = good). Surveys were completed once prior to the next emetogenic chemotherapy treatment both for the acute component and the delayed component, and they were administered by trained personnel. Children who were able to understand and answer the survey questions (typically age 9 yrs and older) were surveyed directly. For younger children, the survey was administered primarily to parents, with input from the child. We defined the acute phase as nausea and emesis that occurred during the days of emetogenic chemotherapy administration. The delayed phase of nausea and emesis was defined as any that occurred on subsequent days. This definition was based on previous literature, which defined delayed nausea and emesis arbitrarily as any that began at least 24 hours after chemotherapy.9
Our practice classified chemotherapy regimens based on antiemetic guideline publications and our own previous experience.2, 3, 12–14 This classification system was used to determine which antiemetic regimen patients received, as described below. In one instance, a chemotherapy regimen (high-dose cytarabine) initially was classified as moderately emetogenic, but it was moved into the severely emetogenic category after there was a poor response to our initial antiemetic strategy.
Antiemetic therapy was designed from previous outcomes studies that were conducted in our patient population and from reports in the literature.3, 11–14 For moderately emetogenic chemotherapy, patients received ondansetron (Zofran; GlaxoSmithKline, Research Triangle Park, NC) at a dose of 0.3 mg/kg intravenously (i.v.) administered once daily during each day of chemotherapy. For the severely emetogenic chemotherapy courses, patients received ondansetron at a dose of 0.45 mg/kg i.v. plus dexamethasone at a dose of 10 mg/m2 i.v., both administered once daily. When high-dose cytarabine was reclassified as severely emetogenic, some patients received dexamethasone 10 mg/m2 i.v. every 12 hours on each day of chemotherapy. These antiemetic regimens were included in the standing chemotherapy orders to improve ordering consistency. Rescue antiemetic therapy was given based on physician discretion but did not include repeated dosing of 5-HT3 antagonists or dexamethasone. Data regarding rescue antiemetic therapy were not collected.
We combined similar chemotherapy regimens in which the same emetogenic chemotherapy agents and antiemetic regimens were used. Specific chemotherapy regimens that were combined are listed in Table 1. Data for survey variables were tabulated within each chemotherapy protocol for each patient by using mean scores among patients who received multiple courses of the same chemotherapy protocol. The mean (± standard deviation) and median scores for all survey variables were calculated for these combined chemotherapy regimens.
|Moderately emetogenic chemotherapy|
|low-dose cytarabine + daunorubicin|
|cytarabine, 150.0 mg/m2 × 3 d + daunorubicin, 30.0 mg/m2 d 1 + 4|
|daunorubicin, 20 mg/m2, cytarabine, 200 mg/m2 c.i. × 4 d, etoposide 100 mg/m2 daily × 4; cytarabine IT, dexamethasone 6 mg/m2 PO × 4 d|
|daunorubicin or doxorubicin|
|daunorubicin, 30.0 mg/m2 plus vincristine|
|doxorubicin, 30 mg/m2 + vincristine|
|doxorubicin, 25 mg/m2; IT methotrexate; vincristine|
|high dose cytarabine|
|cytarabine, 3 g m/m2 q12h × 4 doses|
|low dose cytarabine|
|cytarabine, 75 mg/m2 daily × 4 days|
|methotrexate, 100 mg/m2iv, IT methotrexate, asparaginase, vincristine|
|TIT = IT methotrexate, hydrocortisone and cytarabiine2|
|methotrexate 1 gm/m2|
|methotrexate, 1 gm/m2 + IT methotrexate|
|methotrexate, 1–2.5 gm/m2 + mercaptopurine, 1 gm/m2|
|methotrexate, 1 gm/m2, mercaptopurine, 1 gm/m2|
|methotrexate, 2.5 gm/m2 + mercaptopurine 1 gm/m2|
|methotrexate, 2 g/m2|
|methotrexate, 2 gm/m2|
|methotrexate, 2 gm/m2|
|methotrexate 2 gm/m2 + IT methotrexate|
|methotrexate 5 gm/m2 + doxorubicin|
|methotrexate, 5 gm/m2, doxorubicin, 30 mg/m2, vincristine, asparaginase, mercaptopurine PO + prednisone, 120 mg/m2 daily × 5 days|
|daunorubicin or doxorubicin combined with corticosteroids|
|daunorubicin, 30 mg/m2 + vincristine + asparaginase + dexamethasone 6.0 mg/m2 × 7 days|
|daunorubicin, 30 mg/m2, IT methotrexate, vincristine, prednisone, 40 mg/m2 × 7 days + asparaginase|
|daunorubicin, 30 mg/m2, TIT, vincristine, prednisone 40 mg/m2 × 7 days + asparaginase|
|doxorubicin, 30/m2 + prednisone, 120 mg/m2 × 5 days + vincristine|
|doxorubicin, 30/m2 + prednisone 120 mg/m2 × 5 days + vincristine + mercaptopurine PO|
|doxorubicin, 30 mg/m2 × 2 days, prednisone, 40 mg/m2 × 7 days, TIT, vincristine + PEG asparaginase|
|Severely emetogenic chemotherapy|
|cytarabine 3 gm/m2 q12h × 4 doses|
|carboplatin, 175 mg/m2|
|carboplatin + etoposide|
|carboplatin, 18.7 mg/kg (560 mg/m2) × 1, etoposide, 3.3 mg/kg (100 mg/m2) × 3 d + vincristine|
|cisplatin ≥ 90 mg/m2|
|cisplatin, 120 mg/m2, doxorubicin 75 mg/m2 c.i. × 72 h|
|cisplatin 40 mg/m2 × 5 days, etoposide 100 mg/m2 × 5 days, bleomycin|
|cisplatin, 50 mg/m2 × 4 days, etoposide 200.0 mg/m2 × 3 days|
|cisplatin, 90 mg/m2 + doxorubicin 80 mg/m2 c.i. × 96 h|
|cyclophosphamide 2 gm/m2|
|cyclophosphamide, 1 gm/m2 × 2 + vincristine|
|cyclophosphamide, 2.2 gm/m2|
|cyclophosphamide, ≥ 1 gm/m2|
|cyclophosphamide 1 gm/m2, cytarabine 75 mg/m2 daily × 4, IT methotrexate + mercaptopurine PO|
|cyclophosphamide, 250 mg/m2 × 5 days + topotecan, 0.75 mg/m2 × 5 days|
|cyclophosphamide 2.1 gm/m2 + doxorubicin or dactinomycin|
|cyclophosphamide 2.1 gm/m2 × 2 + doxorubicin 25 mg/m2 × 3 + vincristine|
|cyclophosphamide 2.2 gm/m2, dactinomycin, 1.25–1.5 mg/m2 + vincristine|
|cyclophosphamide + doxorubicin ± etoposide + bleomycin|
|cyclophosphamide, 1 gm/m2, carboplatin, 560 mg/m2, doxorubicin 30 mg/m2|
|doxorubicin, 25 mg/m2 × 2, etoposide 125 mg/m2 × 3, cyclophosphamide, 800 mg/m2, bleomycin, vincristine + prednisone|
|doxorubicin 30 mg/m2 × 2, cyclophosphamide 800 mg/m2, etoposide 75 mg/m2 × 5, bleomycin + prednisone 40 mg/m2 × 10 days|
|cyclophosphamide 1.2 gm/m2, doxorubicin 75 mg/m2, + vincristine|
|dactinomycin 45 mcg/kg (1.35 mg/m2)|
|ifosfamide + etoposide ± carboplatin|
|etoposide 100 mg/m2 × 3, ifosfamide 1.8 gm/m2 × 3 + carboplatin, (560 mg/m2 × 1)|
|ifosfamide 1.8 gm/m2 + etoposide 100 mg/m2 × 5 days|
|ifosfamide 3.4 gm/m2 × 3 days + etoposide 100 mg/m2 × 3 days|
|methotrexate 12 gm/m2|
|methotrexate 12 gm/m2|
|cyclophosphamide > 1 gm/m2 ± etoposide|
|cyclophosphamide 33 mg/kg (1 gm/m2) × 1 + etoposide 4 mg/kg (120 mg/m2) × 3|
|cyclophosphamide 1.2 g/m2 + vincristine|
We defined complete protection (CP) as the percentage of patients who had both nausea and emesis scores of zero. This was accomplished by analyzing CP data from each course of each different chemotherapy regimen for each individual patient. CP rates were calculated for each chemotherapy regimen during both the acute and delayed phases and were calculated separately for regimens that were judged moderately and severely emetogenic. We determined rates of CP by gender and age group with 3 categories for age-group analysis: the toddler group (ages birth–3 yrs), the elementary group (ages 4–11 yrs), and the adolescent group (ages 12–20 yrs). These age groups were chosen based on what are considered natural dividing lines for comparing patients of different ages. In addition, CP rates were compared between children ages 9 years and older with younger children to determine whether parental ratings had an influence on survey scores. We compared rates of CP between males and females and among the three age groups. Based on initial trends in the data, subsequently, we compared CP rates between the toddler age group and the older children (the elementary and adolescent groups combined).
Analyses were performed to compare CP in the acute phase with CP in the delayed phase. These analyses were performed for all patients during the first and second courses of chemotherapy, overall, and for moderately and severely emetogenic regimens. We performed an analysis of all courses of chemotherapy (by course) to determine whether acute CP was associated with CP in the delayed phase. In addition, CP rates for nausea and emesis were compared for both moderately and severely emetogenic regimens of each patient's first course of a chemotherapy regimen.
Chi-square analyses were used to identify significant differences in CP. Fisher exact tests were used to identify significant differences when appropriate (expected frequency, < 5 in ≥ 1 cells). The α level was P < 0.05, with Bonferroni, family-wise adjustments for repeated tests.
In total, 1256 surveys were performed in 224 different patients from October 1998 to December 2003. The patient demographics are provided in Table 2. The most commonly encountered diagnoses are presented along with the distribution by age and gender. This distribution of diagnoses mirrors the approximate proportions of malignancies in the pediatric population for which chemotherapy commonly is employed.15 The overall age distribution of these patients also is provided in Table 2 along with the percentage of regimens received by each age group that were judged moderately and severely emetogenic. There were more males than females across all age categories, and the adolescent group received a greater percentage of severely emetogenic chemotherapy regimens than the other two age groups. There were no differences between genders in the percentage of severely emetogenic regimens that were surveyed.
|No. of patients||Percent of patients||No. of patients|
|Females||Males||Toddler (ages birth–3 yrs)||Elementary (ages 4–11 yrs)||Adolescent (ages 12–19 yrs)|
|Most common diagnoses|
|Chemotherapeutic emetogenicity (%)|
|Total no. of surveys (%)|
|Females||152 (38.6)||204 (39.2)||92 (26.9)|
|Males||242 (61.4)||316 (60.8)||250 (73.1)|
Control of Nausea and Emesis
The rates of CP for each patient's initial course of each chemotherapy regimen are provided in Table 3. These data are presented by age group and gender for the acute and delayed phases and for both moderately and severely emetogenic regimens. The CP rates were found to be greater in the acute and delayed phases for moderately emetogenic regimens. There were no differences in CP between genders and among the three age groups, although there were trends for toddlers to have greater nausea and emesis control. Further analysis to compare complete control rates between toddlers and older children (the elementary and adolescent groups combined) did reveal significant differences. Toddlers had greater CP in the acute phase for moderately emetogenic chemotherapy (83.1% vs. 69.6%; P = 0.032) and severely emetogenic chemotherapy (65.7% vs. 42.2%; P = 0.019). In addition, for the delayed phase of severely emetogenic regimens, CP rates for toddlers approached statistical significance (65.7% vs. 45.1%; P = 0.05). Figure 1 summarizes CP rates by 3-year age ranges for each patient's initial course of each chemotherapy regimen and displays a decrease in CP as children grew older.
|Category||Acute CP rate (%)||Delayed CP rate (%)|
|Moderate EMET||Severe EMET||Moderate EMET||Severe EMET|
|Rate (%)||No. (CP/overall)||Rate (%)||No. (CP/overall)||Rate (%)||No. (CP/overall)||Rate (%)||No. (CP/overall)|
|Toddler (ages birth–3 yrs)||83.1||64/77||65.7||23/35||72.6||56/77||65.7||23/35|
|Elementary (ages 4–11 yrs)||73.1||87/119||39.1||18/46||61.3||73/119||43.5||20/46|
|Adolescent (ages 12–20 yrs)||63.9||46/72||44.6||25/56||70.8||51/72||46.4||26/56|
The CP rates varied among the moderately emetogenic regimens. We noted that high-dose i.v. cytarabine, low-dose cytarabine with daunorubicin, the i.v. methotrexate plus mercaptopurine combination, and the combination of methotrexate (at a dose of 5 mg/m2) with doxorubicin all had complete control rates of approximately ≤ 50% in the acute and/or delayed phases. This may have been due to residual mild nausea that was not controlled adequately by the antiemetic regimen. In addition, 7 of 12 different types of severely emetogenic chemotherapy regimens had CP rates < 50% in either the acute phase or the delayed phase. CP rates were particularly low for cisplatin (20% for Course 1 during the acute and delayed phases) and for cyclophosphamide combined with doxorubicin or dactinomycin (30–36% in the acute phase; 21–55% in the delayed phase). To further determine the pattern of CP rates over time, data are presented in Figure 2A,B for regimens in which at least five different patients were surveyed for at least four courses of the same chemotherapy regimen. These data demonstrate that CP rates did not tend to worsen over time. Variability in CP was noted for regimens that included smaller numbers of patients.
The comparison of complete control rates between nausea and emesis for each patient's initial course of chemotherapy revealed that nausea control was less in the acute phase (73.2% vs. 86.7%; P ≤ 0.001) and the delayed phase (69.4% vs. 79.7%; P ≤ 0.001) for moderately emetogenic chemotherapy. Results were similar for initial courses of severely emetogenic regimens, with lower control of nausea in both the acute phase (63.0% vs. 70.4%; P = 0.028) and the delayed phase (65.3% vs. 74.0%; P = 0.008).
The analysis of CP rates by comparing patients age 9 years and older with patients younger than age 9 years revealed a significant difference in CP in the acute phase for severely emetogenic chemotherapy, with an improved response observed in younger children (58.5% vs. 38.9%; P = 0.022). However, when CP rates were compared for nausea (e.g., nausea CP) and emesis separately between these two age groups, there were no differences for either variable with moderately or severely emetogenic regimens. Within individual chemotherapy regimens, differences were found with three regimens; for two of these three regimens, CP rates were greater in younger children.
Acute Control versus Delayed Control
For each patient's first and second courses of chemotherapy with each different regimen, CP rates were similar in the acute and delayed phases (64.9% vs. 61.5%, respectively, for Course 1). There also were no differences in CP rates between the acute and delayed phases when data were analyzed further for moderately and severely emetogenic regimens among the 3 age groups or by gender (Table 3). In the overall data set, acute CP was associated with delayed CP. Among courses with CP in the acute phase (n = 835 courses), CP was more frequent in the delayed phase (n = 637 courses; 76.3%). Among courses that were not protected in the acute phase (n = 421 courses), there was significantly lower CP (P < 0.001) in the delayed phase (n = 155 courses; 36.8%).
Severity of Nausea and Emesis
The survey scores for moderately emetogenic regimens were indicative of less than mild nausea and emesis (mean scores, < 1.0) for both the acute phase and the delayed phase, with the exception of the regimen that consisted of i.v. methotrexate in combination with i.v. mercaptopurine (mean NSEV score, 1.3 for the acute phase and 1.4 for the delayed phase). For these regimens, nausea was more prevalent than emesis, because the mean number of emesis episodes among these regimens was 0.5 ± 1.2 episodes in the acute phase and 1.0 ± 1.9 episodes in the delayed phase. In addition, the median number of emesis episodes was zero with one exception (high-dose cytarabine: median, one emesis episode). Among severely emetogenic chemotherapy regimens, we demonstrated that cisplatin-based chemotherapy (cisplatin ≥ 90 mg/m2) and i.v. cyclophosphamide 2.1 g/m2 combined with either i.v. doxorubicin or dactinomycin had significant nausea and emesis scores (NSEV and VSEV scores, ≥ 1.0) during both the acute phase and the delayed phase despite standard antiemetic prophylaxis. For the severely emetogenic regimens, the mean number of emesis episodes was 1.2 ± 2.6 episodes in the acute phase and 1.2 ± 2.8 episodes in the delayed phase. Likewise, the median number of emesis episodes was 0.0 with the exception of cisplatin (acute phase, 2.5 episodes; delayed phase, 1.5 episodes).
Duration of Symptoms
It was apparent from the results of the current study that, although nausea had been rated below the mild range for moderately emetogenic regimens, it was of fairly long duration. In particular, the median nausea duration was prolonged for regimens with higher doses of i.v. methotrexate (median, ≥ 72 hrs), low-dose i.v. cytarabine (median, 72 hrs), and intrathecal methotrexate (median, 84 hrs). For the severely emetogenic regimens, the median nausea duration was greater for regimens that consisted of methotrexate at a dose of 12 gm/m2 (median, 84 hrs), cisplatin (median, 84 hrs), carboplatin combined with ifosfamide and etoposide (median, 108 hrs), carboplatin with etoposide (median, 72 hrs), and most regimens that contained i.v. cyclophosphamide (median, 74 hrs).
To our knowledge, the current study provides the first comprehensive overview of the efficacy of standard antiemetic therapy in both the acute and delayed phases and across common chemotherapy regimens employed in pediatric oncology. Overall, we found that antiemetic therapy was effective in preventing significant nausea and emesis in children, particularly for moderately emetogenic chemotherapy. However, inadequate control of nausea and emesis in both the acute and delayed phases was documented for several types of chemotherapy regimens, and at least three types of regimens had nausea and/or emesis scores in the moderate range. The CP rates were particularly disappointing for many of the severely emetogenic chemotherapy regimens, especially with regard to the control of nausea. CP rates varied among children, especially in relation to patient age, with the youngest children showing complete control rates significantly superior to those of older children and adolescents. The CP rates were not different in the acute phase versus the delayed phase for either moderately emetogenic or severely emetogenic chemotherapy regimens in this patient population. This most likely reflects the much greater utilization of multiple-day chemotherapy regimens in the pediatric oncology arena. In pediatric oncology, it is likely that these two phases are superimposed on each other when multiple-day regimens are used. This finding indicates that a new paradigm may be needed to characterize accurately and to prevent chemotherapy-induced nausea and emesis among children who receive multiple-day chemotherapy regimens.
The findings from this study reveal some important issues regarding antiemetic studies in the pediatric population. The severity of nausea and emesis did vary between the moderately emetogenic and severely emetogenic chemotherapy regimens. Studies of antiemetic control rates that combine dissimilar emetogenic regimens together to report overall success rates may not be a valid means of describing actual rates of nausea and emesis control in clinical practice.10, 16, 17 This heterogeneity in antiemetic response among different chemotherapy regimens indicates the need for quality improvements and may guide clinicians to focus research on chemotherapy regimens for which antiemetic therapy is inadequate. Potential future studies that can be derived from this research include targeting certain chemotherapy regimens to test newer antiemetic agents (e.g., aprepitant) in children, redefining and/or combining the acute and delayed phases for antiemetic studies in children who receive chemotherapy, and conducting studies to examine markers of chemotherapy-induced nausea and emesis that may predict the heterogeneity in response for children of different ages.
The reasons for greater complete control in the toddler patient population are unclear but are consistent with our previous study of nausea/emesis control rates in children.2 Anxiety and patient perception may be important contributors to nausea and emesis in older children. Data regarding anticipatory nausea and emesis were not collected in the current study, so we could not assess the impact that this may have had among the different age groups. There is recent evidence that cortisol activity is different in early childhood. In particular, the adult cortisol rhythm pattern, with a significant decrease in concentration between mid-morning and mid-afternoon, is not evident in children age 36 months and younger.18 It has been reported that older adults with higher cortisol excretion had less chemotherapy-induced nausea.19 Taken together, our results and previously published reports provide some evidence that endogenous cortisol production may explain in part the relation between age and chemotherapy-induced nausea and emesis at both ends of the age spectrum.
To our knowledge, few studies have been conducted to date to evaluate the performance of standard antiemetic therapy in patients receiving emetogenic chemotherapy. Two large evaluations were performed recently in the adult population.16, 17 One of those studies examined the first 2 courses of i.v. chemotherapy that contained either carboplatin, cisplatin, or doxorubicin and showed that 76% of patients developed some nausea during the first 5 days of receiving their chemotherapy.16 No details were provided in that report regarding the antiemetic regimen(s) employed after Day 1 of chemotherapy. A second study focused primarily on moderately emetogenic chemotherapy and documented acute nausea in > 30% of patients and acute emesis in ≥ 12% of patients.17 During the delayed phase, > 50% of patients reported nausea, whereas emesis was reported by 28%. The reported response rates did not differentiate between the antiemetic regimens that the patients received, and results were limited to the presence or absence of nausea or emesis, with no information provided on the severity of nausea or emesis.
To the best of our knowledge, there has been one study that evaluated the incidence of delayed nausea and emesis among children who were receiving chemotherapy.10 Nausea of moderate-to-severe intensity was reported on 58% of study days. However, those investigators noted that 79% of the chemotherapy cycles studied were not associated with delayed emesis. The high percentage of children without delayed emesis may reflect a lack of significant emetogenic potential among many of these regimens; in 100 of 174 chemotherapy cycles, no antiemetics were administered. In addition to including a majority of regimens with low emetogenic potential, that previous report did not reveal the variability in response among different moderately or severely emetogenic regimens.10
We demonstrated that regimens containing cisplatin or higher dosages of alkylating agents (e.g., cyclophosphamide at a dose > 2 gm/m2) were particularly prone to lower CP rates. Unlike response rates to cisplatin, which have been characterized well, nausea and emesis control rates in patients who receive alkylating agents have been described less.9 In the regimens that we studied that were classified as moderately emetogenic, those containing higher doses of cytarabine or methotrexate also were associated with lower complete control rates. Because of the inadequate response to ondansetron alone, subsequent patients who received high-dose cytarabine also received dexamethasone, which led to an improvement in CP from 44% to 75% during the first course of chemotherapy. Because some of the Pediatric Oncology Group protocols at the time that these data were collected were discouraging antiemetic doses of corticosteroids for children with acute lymphoblastic leukemia, those patients who received higher doses of methotrexate were not managed with dexamethasone. The suboptimal outcomes achieved in these patients likely were the result of the omission of dexamethasone from the antiemetic regimen. With regard to methotrexate, only one of the three commonly cited antiemetic guidelines indicate increased nausea and emesis potential with higher doses of methotrexate.12–14 Because literature supporting these guidelines was based primarily on research in adults, these differences likely reflect the limited experience with high-dose methotrexate in adult oncology. It is evident that certain chemotherapy regimens that are employed primarily in the pediatric population have significant emetogenic potential that has not been documented previously in the literature and that reclassification of some chemotherapy agents (e.g., methotrexate) is necessary.
We acknowledge there are limitations to the current study. Due to the large number of rotational treatment strategies employed in the pediatric arena, there were small numbers of patients surveyed for some of the chemotherapy regimens. This is reflected in the variability of some of our estimates, but it does not affect our overall conclusions. The accuracy of our survey results may be reduced in patients younger than age 9 years for whom parents provided some of the survey responses. However, in subsequent analyses, we found only one difference in complete control, and no differences were observed in the control rates for nausea or emesis individually when we compared children younger than age 9 years with older children. Therefore, we conclude that parents exerted minimal bias on the nausea or emesis ratings of younger children. Furthermore, parental history is the primary health information source for younger children. Our data reflect usual practice, and other research has demonstrated that parental history closely approximates the younger child's actual experience with nausea and emesis.20, 21 With regard to the timing of our survey administration, it is possible that some patients and/or parents did not recall accurately the nausea or emesis that may have occurred from the previous cycle of chemotherapy. In our experience, patients and parents have good recall when the survey is administered within a few weeks of completion of chemotherapy, which is our standard practice. We did not track utilization of antiemetic rescue medications; therefore, we do not know whether this may have influenced nausea and emesis scores in some patients. Because these medications are received by patients who already have failed, they would not influence CP rates. We also are unaware of any controlled trials that demonstrate an improvement in efficacy when rescue medications are used in this setting. Finally, we acknowledge that the CP rates in this study may have been influenced by our daily dosing schedule of ondansetron. However, previous outcome studies in pediatric oncology revealed that a daily dosage of ondansetron of 0.45 mg/kg was as effective as or more effective than a divided dosing strategy (ondansetron at a dose of 0.15 mg/kg every 4 hrs × 3 doses).3 It is unclear whether lower doses of ondansetron (0.15 mg/kg × 1 dose) may have resulted in similar effectiveness for children who received these chemotherapy regimens.
The results of the current study have demonstrated that rates of complete nausea and emesis control are low among children who are receiving several types of commonly administered chemotherapy regimens. In particular, even with “usual care” antiemetic prophylaxis, chemotherapy regimens that contained either cisplatin or higher doses of alkylating agents, methotrexate, or cytarabine had low rates of CP in either the acute phase and/or the delayed phase. CP rates were found to be associated significantly with patient age, with higher CP rates observed in very young children. These data indicate that nausea and emesis remain significant problems among children who are receiving certain chemotherapy regimens and that guidelines for the management of nausea and emesis do not reflect accurately the emetogenic potential of some of these regimens in the pediatric population.
The authors thank C. J. Laselute for her work on the tables and figures for this article.
- 4Italian Group for Antiemetic Research. Cisplatin-induced delayed emesis: pattern and prognostic factors during three subsequent cycles. Ann Oncol. 1994; 5: 585–589.
- 8Italian Group for Antiemetic Research. Prevention of cisplatin-induced delayed emesis: still unsatisfactory. Support Care Cancer. 1999; 8: 229–232.
- 11Assessment of chemotherapy-induced emesis and evaluation of a reduced-dose intravenous ondansetron regimen in pediatric outpatients with leukemia. Ann Pharmacother. l995; 29: l6–2l., , , , .
- 12ASHP Commission on Therapeutics. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm. 1999; 56: 729–764.
- 14Multinational Association for Supportive Care in Cancer. Antiemetic guidelines. March, 2004. Available at URL: http://www.mascc.org [accessed May 15, 2005].