Department of Pharmacy, Klinikum rechts der Isar, Technische Universitt Mnchen; 2MERG, Medical Economics Research Group, Munich;
Third Medical Department, Klinikum rechts der Isar, Technische Universitt Mnchen, Germany; 4Merck & Co., Inc., Whitehouse Station, NJ, USA;
5
Department of Clinical Pharmacology, University of Vienna Medical School, Vienna, Austria
3
cancer chemotherapy. We assessed, under current practice patterns, the occurrence and impact on healthcare
resource utilization of CINV in patients receiving emetogenic chemotherapy. An additional aim of this study
was to estimate costs imputable to CINV in the German healthcare environment.
Materials and methods: This prospective, multi-center, cross-sectional cost-of-illness study was conducted
in three hospitals and in three office-based facilities in Germany. Consecutive patients undergoing emetogenic
chemotherapy (levels 4 or 5 according to Hesketh classification of emetogenicity) were enrolled. Data were
obtained from preplanned chart reviews and from self-administered patient questionnaires. Analysis of direct
costs was performed from the perspectives of third party payer (statutory sick fund), provider (hospital) and
patients. Indirect costs were assessed on the basis of paid workdays lost.
Results: During the 5-day observation period, 134 of 208 chemotherapy cycles observed (64.4%) were associated
with at least one episode of nausea or vomiting. More patients experienced delayed than acute CINV (60.7%
versus 32.8%), and more patients reported nausea than vomiting (62.5% versus 26.0%). A total of 68 patients
(32.6%) utilized healthcare resources due to CINV. The most frequently used resources were rescue medications and outpatient hospital and office physician visits. Only one patient required hospitalization and only three
patients lost workdays due to CINV. Average costs imputable to CINV per patient (with or without CINV) per
treatment cycle incurred by third party payers and hospital providers were $49 and $48, respectively. Patient or
treatment characteristics that were associated with high costs imputable to CINV were as follows: cisplatincontaining regimen; experience of emesis; and presence of delayed CINV.
Conclusions: A substantial proportion of patients continue to experience CINV. This entails not only clinical
but also economic consequences, and highlights a continuing need for improved utilization of existing
antiemetic agents and for new, more efficacious treatments. The greatest improvements in patient care and
potential for cost offset may be realized by preventing delayed CINV.
Key words: chemotherapy-induced nausea and vomiting, cost-of-illness, healthcare utilization, health
economics, healthcare provider, third party payer
Introduction
Chemotherapy-induced nausea and vomiting (CINV) remains a
major adverse effect of cancer chemotherapy, despite the availability of several antiemetic drug classes, including 5-HT3 receptor
antagonists. Although not life-threatening, CINV has a major
impact on a patients quality of life and ranks high on the list of
factors most feared by patients receiving chemotherapy [1].
Background: Delayed chemotherapy-induced nausea and vomiting (CINV) remains a major adverse effect of
527
impact and costs of CINV in clinical practice, as opposed to clinical
trial settings, is of importance for allocating resources to existing
and novel antiemetic drug regimens. There are many reports on
the incremental cost-effectiveness of antiemetic drugs, but information on the total cost per patient associated with CINV is limited
[3]. Moreover, cost-of-illness data cannot necessarily be directly
extrapolated from one country to another because of differences in
treatment practice, drug regimens and drug dosages [4], as well as
drug and labor costs [5].
Against this background, we set out to prospectively assess,
under current practice patterns, the occurrence and impact on
health resource utilization of CINV in patients receiving emetogenic
chemotherapy. Additional aims of this study were to estimate the
direct and indirect costs of CINV in the German healthcare
environment, and to identify characteristics of patient subgroups
that are associated with high costs imputable to CINV.
Data collection
Data were obtained from preplanned, structured chart reviews and from selfadministered patient questionnaires. Chart data were abstracted by trained and
experienced staff (e.g. a study nurse) of the Department of Pharmacy at the
Klinikum rechts der Isar, Technische Universitt Mnchen (MRI), or Medical
Economics Research Group (MERG), Munich.
Data extracted from medical charts included the following: patient demographics; clinical history and co-morbidity; clinical condition requiring
chemotherapy; details of chemotherapy regimen and antiemetic prophylaxis
and treatment; detailed vomiting and nausea experience during hospitalisation; and healthcare resource consumption due to vomiting and nausea.
Patients were surveyed in the following areas: day-by-day experience of
nausea and vomiting (frequency/level of severity; days 15); physician visits
or hospitalisations required due to CINV; expenses incurred for over-thecounter (OTC) medication, transportation or home help required due to CINV;
employment status; workdays lost due to CINV.
For the purpose of this analysis, acute CINV was defined as at least one
episode of nausea and/or vomiting during the first 24 h after the beginning of
chemotherapy administration [2]. Delayed CINV was defined as at least one
episode of nausea and/or vomiting that occurred >24 h after the beginning of
chemotherapy administration, irrespective of the presence or absence of acute
CINV in that patient.
An emetic episode was defined as one episode of vomiting or a sequence of
productive or unproductive retching episodes in very close succession. Severity
of emesis was based on the NCICTC guidelines [6]. Patients were asked to
rate their level of nausea on a three-point Likert scale (mild, moderate, severe).
that had provoked emesis and/or nausea as defined by the National Cancer
Institutecommon toxicity criteria (NCICTC) [6] grade >0 for vomiting, and
grade >2 for nausea; relevant previous CINV experience as defined by NCICTC
[6] grade >0 for vomiting, and grade >2 for nausea; previously diagnosed CNS
metastasis or primary CNS cancer; pregnancy. Patients receiving routine medication with emetic or antiemetic properties (e.g. opioids, butyrophenones)
were not explicitly excluded. One to five per cent of patients received concomitant medications with antiemetogenic or emetogenic properties, depending on
substance type. Because in most cases these medications were not prescribed
routinely (with the exception of opioids containing pain medication), no further
analysis was performed.
Written informed consent was obtained from all patients; the study was
approved by the ethics committee of the Medical Faculty of the Technische
Universitt Mnchen, Germany.
528
Unit costs were estimated from several different sources, depending on the
payer perspective. Cost data sources were as follows:
Results
Statistical analysis
The statistical analysis software package SAS, version 8.0 (Cary, NC, USA)
was used for the analysis of data. Descriptive statistics (mean, median, minimum,
maximum and standard deviation) were calculated for each cost item. Differences
in frequencies or scores were tested by the chi-square test and MannWhitney
U-test, respectively.
Average (per patient) costs per chemotherapy cycle were calculated separately for prophylaxis, treatment and overall management (i.e. prophylaxis plus
treatment) of CINV, for those cycles that were associated with an experience
of CINV and for all cycles (with and without CINV). Differentiation between
these samples is important because patients not experiencing CINV still
incurred the costs of prophylaxis.
Differences in the cost of CINV were explored across several subgroups of
patients. These were based on the following criteria: cisplatin/non-cisplatincontaining regimen; chemotherapy treatment cycle; level of CINV; presence
of delayed CINV; and adherence to the American Society of Clinical Oncologists
(ASCO) guidelines [2] for prophylaxis of delayed CINV.
The provider perspective was not calculated for the office-based treatment
settings because data regarding staff time and administration costs are lacking.
529
Cost of CINV
The average cost per treatment cycle resulting in an experience of
CINV, incurred by third party payers and by patients, as well as
the indirect costs, are detailed in Table 5. The corresponding cost
figures from the perspective of the provider (hospital) are presented in Table 6.
In Tables 5 and 6, costs are given as the mean cost per treatment
cycle for two different groups, those patients who experienced
CINV, and all patients. The acquisition and administration costs
for antiemetic drugs are separated for prophylactic and treatment
(rescue) use, to account for the fact that even patients not experiencing CINV still incurred the costs of prophylaxis [3].
We conducted several subgroup analyses from the hospital provider perspective to identify patient or treatment characteristics
that were associated with high costs imputable to CINV (Table 7).
These characteristics were as follows: cisplatin containing regimen;
experience of emesis; and presence of delayed CINV (P <0.05
versus reference group).
Non-adherence to ASCO guidelines for delayed CINV was
associated with slightly higher cost, but the difference did not
reach the level of significance. The cost of CINV for patients studied
during cycle four of their chemotherapy was not statistically
significantly different from cycle-one patients.
Discussion
The goal of antiemetic treatment is to prevent nausea and vomiting
completely [2]. However, despite improvements and considerable
research efforts, this goal is still elusive for a significant number of
patients. Results from our prospective study support the concept
that CINV remains a relevant adverse effect of chemotherapy in
daily clinical practice. A majority of patients (64.4%) experienced
at least one episode of nausea or vomiting, even though all of them
530
Table 1. Type of malignancy and chemotherapy (n = 188 patients)a
Treatment setting, n (%)
Hospital-based setting
Office-based setting
All patients
(n = 122)
(n = 66)
(n = 188)
Type of malignancy
Gastrointestinal
64 (52.5)
9 (13.6)
73 (38.8)
Breast
17 (13.9)
36 (54.6)
53 (28.2)
Lung
21 (17.2)
6 (9.1)
27 (14.4)
3 (2.5)
6 (9.1)
9 (4.8)
10 (8.2)
6 (9.1)
16 (8.5)
7 (5.7)
3 (4.6)
10 (5.3)
Cisplatin
69 (56.7)
2 (3.0)
71 (37.8)
Carboplatin
11 (9.0)
15 (22.7)
26 (13.8)
Oxaliplatin
9 (7.4)
5 (7.6)
14 (7.4)
Epirubicine
Ovarial
Lymphoma
Other
Chemotherapy
17 (13.9)
24 (36.3)
41 (21.8)
Doxirubicine
8 (6.6)
10 (15.2)
18 (9.6)
Cyclophosphamide
5 (4.1)
7 (10.6)
12 (6.4)
Other
3 (2.5)
3 (4.5)
6 (3.2)
For chemotherapy combinations, the agent with the greatest emetogenic risk is shown.
531
Table 2. Prophylactic antiemetic treatments
Antiemetic agents used for prophylaxis
of acute emesis (n = 204 cycles)a
5-HT3/corticosteroid
Cycles, %
Percentage of cycles
with acute CINV
Yes (89.2)
33.0 (N and/or V)
75.0
5-HT3/corticosteroid/H1
9.8
5-HT3/corticosteroid/D2
4.4
5-HT3
6.8
5-HT3/H1
0.5
5-HT3/D2
0.5
D2
0.5
Corticosteroid
2.0
Corticosteroid/D2
0.5
No prophylaxis
9.3 (V)
No (10.8)
31.8 (N and/or V)
9.1 (V)
0.0
100
(100)
Cycles, %
Yes (49.2)
49.5* (N and/or V)
Corticosteroid/5-HT3
6.9
Corticosteroid/5-HT3/H1
0.5
Corticosteroid/5-HT3/D2
30.8
Corticosteroid
8.0
Corticosteroid/H1
0.5
Corticosteroid/D2
5-HT3
2.5
21.9
5-HT3/D2
2.5
5-HT3/H1
0.5
D2
10.9
D2/H1
No (50.8)
0.5
b
1.0
No prophylaxis
13.5
Corticosteroid
11.1* (V)
100
71.6 (N and/or V)
33.3 (V)
(100)
Four and seven cycles, respectively, with missing values regarding onset of acute or delayed symptoms.
Patients in this group received a cisplatin-containing regimen.
*P >0.005 versus patients receiving antiemetic regimen not in agreement with ASCO guidelines.
ASCO, American Society of Clinical Oncology; CINV, chemotherapy-induced nausea and vomiting; D2, dopamine2-receptor
antagonists; H1, histamine1-receptor antagonists; 5HT3, 5-hydroxytryptamine3-receptor antagonists; N, nausea; V, vomiting.
532
Table 3. Frequency and severity of acute and delayed chemotherapy-induced nausea and vomiting (n = 208 cycles)
Grade of nausea and vomiting
Total No. of
cycles, n (%)
(n = 204)
(n = 201)
(n = 208)
22 (10.8)
34
42 (20.9)
45 (21.6)
6 (3.0)
6 (3.0)
7 (3.4)
28 (13.7)
48 (23.9)
52 (25.0)d
Mild
17 (8.3)
41 (20.3)
48 (23.1)
Moderate
22 (10.7)
44 (21.9)
44 (21.2)
Severe
27 (13.2)
33 (16.4)
37 (17.8)
All grades
66 (32.3)
118 (58.7)
129 (62.0)e
67 (32.8)
122 (60.7)
134 (64.4)
All grades
Nausea by severity
Table 4. Utilization of healthcare resources and workdays lost due to CINV (total number of evaluable cycles, n = 208)
Type of resource consumption (units)
13 (6.3)
29
20 (9.6)
270
23 (11.1)
28
6 (2.9)
1 (0.5)
1 (0.5)
11 (5.3)
15
15 (7.2)
15
3 (1.4)
NE
3 (10.0)
4.4
533
Table 5. Cost of CINV incurred by third party payers (sick funds) and patients, and indirect costsa
Type of cost
Ambulance transport
Taxi/public transportation
Total
Indirect costs
Workdays losttotal cost per patient
Direct costthird party payer (cost of
prophylaxis plus treatment)
Direct costpatient
Indirect cost
Total
Costs are given as the mean per treatment cycle for two different denominators: cycles associated with CINV
experience, and all cycles. Mean SD [median] costs are presented because the data were not normally
distributed.
b
Includes only rescue medication administered outside hospital, because drugs administered in-hospital are
included in hospital day rates.
c
Cost for prophylaxis in patients receiving chemotherapy at the hospital is calculated at $0, because cost for
prophylaxis is included in the flat rate third party payers reimburse for chemotherapy treatment.
CINV, chemotherapy-induced nausea and vomiting; OTC, over the counter medication.
OTC/alternative medication
534
Table 6. Cost of CINV incurred by provider (hospital)a
Mean cost per treatment cycle per patient in 2002, $
Cycles with CINV (n = 73)
Medication to treat CINV (rescue medication)b
Subtotal
Subtotal
Total
The provider perspective is not calculated for the office-based treatment settings, because data regarding staff time
and administration costs are lacking. Costs are given as means per treatment cycle for two different denominators
(cycles associated with CINV experience, and all cycles), because patients not experiencing CINV during a
particular cycle still incurred the costs of prophylaxis. Mean SD [median] costs are presented because the data
were not normally distributed.
b
Includes only rescue medication administered inside hospital.
535
Table 7. CINV-attributable cost in 2002$ by subgroup (hospital-provider perspective)a
n
Prophylaxis
137
33.72 11.09
14.55 80.62
48.27 81.33
Non-cisplatin
55
26.67 12.70
7.11 18.57
33.79 22.11
1.00 (ref.)
Cisplatin
82
38.44 6.54
19.54 103.05
57.98 102.68
1.72*
No CINV
64
33.52 10.80
0.00
33.52 10.80
1.00 (ref.)
Nausea only
44
34.28 10.30
5.45 10.17
39.73 19.93
1.19
29
33.30 13.11
60.48 169.15
93.77 169.28
2.80*
Emesis level 12
25
33.04 11.88
25.21 23.08
58.26 25.93
1.74
Emesis level 34
37.67 25.67
374.50 478.43
412.17 472.22
12.29
Delayed, no
67
33.36 10.69
33.36 10.69
1.00 (ref.)
Delayed, yes
66
33.81 11.69
29.25 114.61
63.06 115.03
1.89*
Delayed, yes
100
37.04 8.21
6.45 16.31
43.49 21.08
1.00 (ref.)
Delayed, no
37
24.73 12.87
36.46 152.14
61.19 153.40
1.41
All cycles
Treatment
Total (prophylaxis +
treatment)
Normalized total
cost
NA
Cisplatin-containing chemotherapies
Mean SD costs are indicated as per patient per cycle. To facilitate interpretation of cost differences between different patient
subgroups, costs are also expressed as multiples of a designated reference subgroup. Note that these analyses include only results from
patients treated in a hospital setting; patients treated in an office-based care setting were excluded.
b
One cycle with missing values regarding severity of emesis.
c
Four cycles with missing values regarding time of onset of symptoms.
*P <0.05 versus reference group.
CINV, chemotherapy-induced nausea and vomiting; NA, not applicable; ref., reference.
a
that the greatest improvement in patient care and potential for cost
offset may be realized by avoidance of delayed CINV.
Acknowledgements
This study was supported by Merck & Co., Inc., Whitehouse Station, NJ, USA.
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