Original article

Annals of Oncology 15: 526536, 2004

DOI: 10.1093/annonc/mdh110

The impact of delayed chemotherapy-induced nausea and vomiting

on patients, health resource utilization and costs in German cancer
centers
A. Ihbe-Heffinger1*, B. Ehlken2, R. Bernard1, K. Berger2, C. Peschel3, H.-G. Eichler4,5, R. Deuson4,
J. Thdtmann1 & F. Lordick3
1

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

Received 27 August 2003; revised 28 November 2003; accepted 19 December 2003

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].

*Correspondence to: Dr A. Ihbe-Heffinger, Apotheke des Klinikums rechts

der Isar, der Technischen Universitt Mnchen, Ismaninger Strasse 22,
81675 Mnchen, Germany. Tel: +49-89-4140-2219;
Fax: +49-89-4140-6365;
E-mail: Angela.Ihbe-Heffinger@lrz.tu-muenchen.de
2004 European Society for Medical Oncology

Aside from these clinical consequences, CINV has considerable

economic impact. Direct costs include acquisition cost of
antiemetic drugs and administration devices, additional patient
care, such as nursing and physician time, and in some cases,
extended hospitalization or readmission. CINV is often not confined to the acute period (developing within 24 h of receiving
chemotherapy), but may manifest itself as delayed CINV (>24 h
post-chemotherapy), which can persist for several days [2]. Therefore, indirect costs may result from reduced productivity at work
or workdays lost.
Economic analyses, including cost-of-illness studies, receive
increasing attention from healthcare payers and providers to help
inform choices in the delivery of care. Hence, quantifying the

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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.

Study design, setting and perspectives

This prospective, multi-center, cross-sectional cost-of-illness study was conducted in three hospitals and in three office-based facilities in Germany. All
centers were experienced in the administration of cancer chemotherapy. Centers
were selected to allow for enrollment of a broad spectrum of patients requiring
chemotherapy and to represent both hospital- and office-based cancer care
settings which reflect current medical practice in Germany.
Analysis of costs was performed from three perspectives: (a) the third party
payer (Krankenkassen or statutory sick funds), (b) the provider (hospital)
and (c) the patient.

Patient selection criteria

Patients were eligible for inclusion if they were scheduled for treatment with
emetogenic chemotherapy as defined by level 4 or 5 categorization on the
emetogenicity scale proposed by Hesketh et al. [1], or with a level 4 or 5
combination chemotherapy according to the algorithm provided by Hesketh et al.
[1]. All of these agents or combinations are associated with a 60% frequency
of emesis [1]. The Hesketh scale and the corresponding algorithm provide
practical means to predict the acute emetogenicity (24 h after chemotherapy)
of individual chemotherapy agents or combination chemotherapy regimens in
the absence of effective antiemetic prophylaxis [1]. According to the Hesketh
scale, chemotherapy agents can be subdivided into five emetogenic levels:
level 1 (<10% of patients experience acute emesis without antiemetic prophylaxis); level 2 (1030%); level 3 (3060%); level 4 (6090%); and level 5
(>90%). For combination chemotherapy, the emetogenic level was determined by identifying the most emetogenic agent in the combination followed
by an assessment of the relative contribution of the other agents to the overall
level of emetogenicity. In doing so, the following rules apply: (a) level 1
agents do not contribute to the emetogenic level of a combination; (b) adding
one or more level 2 agents increases the emetogenicity of the combination by
one level greater than the most emetogenic agent in the combination; and
(c) adding level 3 or 4 agents increases the emetogenicity of the combination
by one level per agent.
Patients were enrolled either at the start of cycles one or four of their treatment course. The study protocol provided for enrollment of consecutive
patients.
Exclusion criteria were as follows: scheduled chemotherapies that are
known to cause delayed emesis beyond day 5 after the start of chemotherapy
(e.g. 5-day cisplatinetoposidebleomycin for testicular cancer); life expectancy <12 weeks; Karnofsky score <60; presence of gastrointestinal disease

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).

Valuations and cost analysis

Direct medical costs were defined as those of prophylactic or rescue antiemetic
drugs, drug administration devices, personnel time associated with preparing
and administering medication and tending to patients with CINV, extended
hospitalisations or re-hospitalisations due to CINV, hospital outpatient or
physician office visits due to CINV, as well as cost of OTC or complementary
and/or alternative medications. Direct non-medical costs were those for transportation and need for assistance, such as additional childcare. Analysis of
indirect costs was based exclusively on the number of workdays lost due to
CINV.
Costs not included were chemotherapy agents, preplanned office or hospital
visits or hospitalisations for the purpose of chemotherapy administration, and
other patient management costs not directly related to CINV. Diagnostic
laboratory or radiography tests were also not included in the analysis as they
do not generally play a relevant role in the management of CINV; in our
patient sample, the cost for this line item was close to zero (data not shown).
No attempt was made to quantify intangible costs such as the impact of CINV
on a patients quality of life. All costs were calculated in 2002$ and not discounted.

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Patients and methods

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

Provider (hospital) perspective: Bundesangestelltentarif 2003 (BAT; official

tariffs for federal employees; personnel time); pharmacy acquisition cost for
drugs administered in the hospital; DKG-NT, Bd.I: Tarif der deutschen
Krankenhausgesellschaft fr die Abrechnung erbrachter Leistungen und fr
die Kostenerstattung vom Arzt an das Krankenhaus, 2002 [infusion bags and
tubing for intravenous (i.v.) drug administration in the hospital]; Statistisches
Bundesamt: Fachserie 12, Reihe 6.3, 2000, Tab 7.2.1; Kosten je Pflegetag
nach Krankenhaus Typen und Lndern (cost per day of hospitalisation).

Description of patient sample

Third party payer (Krankenkassen, statutory sick fund) perspective:

Einheitlicher Bewertungsmastab (EBM; German tariff list for outpatient
care); Lauer-Taxe: WINAPO Lauer-Taxe, Lauer-Fischer, Germany (acquisition cost for drugs prescribed by or administered in outpatient facilities;
Zahlenbericht 2001/2002 der PKV, Private Krankenversicherer (reimbursable
cost per day of hospitalization).

Patient perspective: Costs incurred by patients were accounted for as

reported by patients in the questionnaire (OTC drugs and complementary and/
or alternative treatments, need for extra childcare, or other assistance, transportation, etc.)
Indirect costs (referring to the societal perspective): The human capital
approach was applied to estimate indirect costs resulting from productivity
losses due to CINV (lost workdays; [7]). On the basis of data for gross wage
and number of persons in dependent employment retrieved from Statistisches
Bundesamt, Germany, the monetary value of productivity loss for employed
persons amounted to $93.74 per day. Lost personal time from daily activities
due to CINV and lost unpaid work due to CINV were not considered.
The number of units of resources consumed were directly obtained from the
medical charts or patient questionnaires.
Personnel time associated with the management of CINV was based on a
publication by Scherbel et al. [8]. These authors quantified, in the German
hospital setting, the average personnel time required for preparation and
administration of injectable antiemetics, and average nursing time and materials
(emesis basins, wash towels, etc.) associated with each episode of vomiting
(for assisting patients with a mouthwash, cleaning, comforting patients and
sometimes changing bed linen and nightwear, etc.). The time required for each
task was multiplied by the average hourly salary and benefits for each group of
professionals.

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.

Frequency and severity of CINV

The frequency and severity of acute and delayed CINV is summarized in Table 3. During the 5-day observation period, 134 of 208
cycles (64.4%) were associated with at least one reported episode
of nausea or vomiting. Delayed CINV was reported more often
than acute CINV (60.7% versus 32.8%), and nausea was reported
more often than vomiting (62.5% versus 26.0%). One patient
withdrew from chemotherapy because of CINV.

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The provider perspective was not calculated for the office-based treatment
settings because data regarding staff time and administration costs are lacking.

A total of 244 patients were enrolled in six centers, 195 patients

(80%) returned questionnaires. The distribution of demographic
and clinical characteristics of responders was similar to that of
non-responders. Questionnaires from seven patients had to be
excluded from the analysis due to incomplete data or protocol
violations. The disposition of the study participants are shown in
Figure 1. Of the remaining 188 evaluable patients, 88 were male,
100 were female; mean age was 55.3 11.2 years; 41.6% of
patients were in the paid work force or self-employed, the remaining
58.4% were retired or unemployed. Among the employed
patients, 53.9% were on sick leave during and after chemotherapy.
Of the 188 patients, 122 and 66 were treated in hospital- and
office-based settings, respectively. Twenty-five patients had
undergone previous courses of chemotherapy treatments previous
to cycle one, but had no relevant previous experience of CINV.
Of 188 patients, 20 were enrolled twice, at the start of cycles one
and four; the remaining patients were studied during one cycle
only, 146 and 42 patients were enrolled at the start of cycles one
and four, respectively. Hence, the total number of cycles studied
was 208.
There were no differences in results (adherence to ASCO guidelines, experience of CINV) from patients studied during their first
treatment cycle, or when results from all cycles, including the
repeat cycles of the 20 patients who were enrolled twice, were
considered. Therefore, all cycles were combined for analysis and
presentation of data.
Diagnoses and chemotherapy regimens are listed by treatment
setting in Table 1. The most frequent diagnoses were gastrointestinal, breast and lung cancers. Patient populations treated in
the hospital and office-based settings were not comparable with
regard to type of malignancy and chemotherapy regimen.
Antiemetic regimens administered for prophylaxis of acute and
delayed CINV, and the association between compliance with
ASCO guidelines [2] and CINV experience, are shown in Table 2.
All patients received prophylactic antiemetic treatment on
day 1, and 89.2% of antiemetic regimens were in compliance with
ASCO guidelines for prophylaxis of acute CINV [2]. 86.5% of
patients received prophylaxis for delayed CINV (>24 h after
chemotherapy), but only 49.2% of the antiemetic regimens were
in compliance with the ASCO guidelines for prophylaxis of
delayed CINV [2].

529

Consumption of healthcare resources and workdays lost

Utilization of health resources and workdays lost due to CINV are
shown in Table 4. A total of 68 patients (33%) utilized healthcare
resources due to CINV (Figure 1). The most frequently used
resources were rescue medications and outpatient hospital and
office physician visits. In contrast, only one patient required hospitalization, and only three patients lost workdays due to CINV.

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

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Figure 1. Disposition of study patients.

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.

received prophylactic medication (Tables 2 and 3). This finding is

in line with previous observational data and results from controlled
clinical trials (for a review, see [9]).
The unsatisfactory therapeutic outcome is driven by a lack of
control of delayed CINV. Twice as many patients experienced
delayed as opposed to acute CINV (Table 3). In part, this is likely
to be the result of suboptimal therapeutic management. More than
50% of patients received a prophylactic regimen for delayed
CINV that was not in agreement with ASCO guidelines, and a
significantly higher proportion of these undertreated patients
experienced delayed CINV than appropriately treated patients
(71.6% versus 49.5%; Table 2). In contrast, 89.2% of patients
received prophylaxis for acute CINV that was in compliance with
ASCO guidelines.
Our findings highlight that, unlike recommendations for the
prevention of acute CINV, guidelines for the prevention of
delayed CINV are still not widely implemented [1013]. The prevention of delayed CINV is recognized to be of equal importance
to the need to prevent acute CINV [2, 14] and, in particular,
improved management of delayed CINV remains a priority. However, our results also show that even optimal management of
CINV is not expected to fully achieve the therapeutic goal: nearly
50% of our patients who were managed according to guidelines
experienced delayed CINV (Table 2).
Our results also show that chemotherapy-induced nausea
affects far more patients than vomiting (62.5% versus 26.0%;
Table 3), which is in line with the notion that the introduction of
5-HT3 receptor antagonists has effected a reduction in the frequency of vomiting, but not in the frequency of nausea episodes
[15]. This is noteworthy since patients, in contrast to physicians

and nurses, typically view control of nausea as more important

than control of vomiting [16, 17]. In aggregate, these findings
highlight the limited effectiveness of currently available
antiemetic prophylaxis, particularly for delayed CINV and nausea
[18], and a need for new pharmacological agents with improved
efficacy.
A further aim of this study was to estimate costs imputable to
CINV so as to provide information for future decisions on
resource allocation. We separately present data on consumption of
healthcare resources (Table 4) and cost data (Tables 5 and 6), to
facilitate the application of our findings to cost analyses in other
healthcare settings where unit costs may differ. Most line items
shown in Table 4 and their relative contributions to overall cost
probably lend themselves to extrapolation to other healthcare
environments. Corresponding data from a similar analysis
conducted in Canada were broadly comparable to our findings [3],
including the small number of patients requiring hospitalization
due to CINV.
However, the small number of workdays lost, and the low indirect
cost resulting from this observation, may not be readily applicable
to other healthcare settings. In our sample, only three of those
patients who experienced CINV and were expected to work lost a
total of 4.4 paid workdays (~35 working hours). OBrien et al. [3]
found that, among 72 Canadian patients experiencing CINV, there
were total losses of 198 h of paid employment and 409 h of unpaid
employment, which explained the fact that, in their study, indirect
cost accounted for about two-thirds of the total cost of CINV.
Similarly, Lindley et al. [19] reported that 23% of their patients
surveyed in a US cancer care center, were unable to go to work
due to emesis.

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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

Antiemetic regimen in agreement with

ASCO guidelines for acute emesis? (%)

9.3 (V)

No (10.8)

31.8 (N and/or V)
9.1 (V)

0.0
100

(100)

Antiemetic agents used for prophylaxis

of delayed emesis (n = 201 cycles)a

Cycles, %

Antiemetic regimen in agreement with

ASCO guidelines for delayed emesis? (%)

Percentage of cycles with

delayed CINV

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)

Total No. of patients, %

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.

The discrepancy may be attributable to differences in data

accrual (e.g. unable to go to work need not be the same as counting
actual workdays lost) or valuation of non-marketed labor time lost
[3]. However, it might also be ascribed to true differences in local
practice regarding sick leave. Most of the patients in our sample
were on sick leave for the period during and after chemotherapy,
irrespective of the occurrence of nausea or vomiting. This, and the
fact that a majority of our patients were retired or unemployed,
necessarily limited the impact of CINV on lost workdays in our
study. Hence, this finding may be limited in scope to German settings.
Quantification of costs imputable to CINV is not straightforward
in a setting where some patients receive chemotherapy in hospitals
while others are seen in office practices. Unit prices are not always

consistent across settings because hospitals often receive special

discounts from manufacturers. Even more complicating, though,
is the reimbursement structure currently in force in Germany. This
implies, for example, that hospitals receive a lump sum per day of
hospitalization from the third party payer (sick funds). The sum is
not related to the actual amount of, for example, antiemetic medication or staff time required. Hence, when hospital patients
require additional CINV treatment, the hospital provider, but not
the third party payer, incurs extra drug and personnel costs. In
contrast, when patients receive rescue medication in an office
setting, the third party payer will reimburse drugs, while the provider incurs no drug costs. This necessitates separate calculation
of costs for different perspectives and patient groups, and, for
quantification of average cost per patient incurred by the third

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Total No. of patients, %

532
Table 3. Frequency and severity of acute and delayed chemotherapy-induced nausea and vomiting (n = 208 cycles)
Grade of nausea and vomiting

Acute (24 h post

chemotherapy), n (%)a,c

Delayed (>24 h post

chemotherapy), n (%)b,c

Total No. of
cycles, n (%)

(n = 204)

(n = 201)

(n = 208)

Vomiting by NCI grade

12

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

Any nausea and/or vomiting

Including patients with or without delayed symptoms.

Including patients with or without acute symptoms.
c
Four and seven cycles, respectively, with missing values regarding onset of acute or delayed symptoms.
d
Two cycles with missing values regarding severity of vomiting; in total, 54 cycles (26.0%) with vomiting.
e
One cycle with missing values regarding severity of nausea; in total, 130 cycles (62.5%) with nausea.
NCI, National Cancer Institute [6].
b

Table 4. Utilization of healthcare resources and workdays lost due to CINV (total number of evaluable cycles, n = 208)
Type of resource consumption (units)

No. of cycles patients utilizing resources/

reporting lost workdays, n (%)

Total No. of units consumed/full

workdays lost

Rescue medication i.v. (dosages)

13 (6.3)

29

Rescue medication oral & rectal (dosages)

20 (9.6)

270

Office physician visits (individual visit)

23 (11.1)

28

Hospital outpatient visits (individual visit)

6 (2.9)

(Extended) hospitalization (days)

1 (0.5)

Ambulance transport (rides)

1 (0.5)

OTC/alternative medication (purchases)

11 (5.3)

15

Taxi/public transportationa (rides)

15 (7.2)

15

Extra home help/childcare (episodes)

3 (1.4)

NE

Workdays lost (full-day equivalents)b

3 (10.0)

4.4

Patient out-of-pocket payment.

Based on 30 cycles where patients are expected to work (patients are not retired and had no sick leave due to chemotherapy).
CINV, chemotherapy-induced nausea and vomiting; i.v., intravenous; NE, not evaluated; OTC, over-the-counter medication.

party payer, requires data from different settings. We therefore

attempted to recruit a case mix of patients from different types of
treatment centers.
The major cost driver from a sick funds perspective was the
acquisition cost of antiemetic drugs for prophylaxis and treatment
of CINV ($40.27 of a total cost of $48.66 per patient; Table 5); as
described earlier, this was incurred exclusively in the office-based
setting. Given the German reimbursement structure, it is not surprising that the main cost driver for hospital providers was staff
time and, to a small extent, drug administration devices and other
materials ($29.94 of a total cost of $48.27 per patient; Table 6).

More importantly, nearly one-third of the total cost per patient

imputable to CINV was due to the treatment of CINV. This was
true for both the third party payer and the hospital-provider perspectives, and represents the potential for cost offset that might be
saved by improved management of CINV.
Out-of-pocket payments by patients and indirect costs represent
only a comparatively small fraction of the total cost of CINV in
our sample.
We have not estimated CINV cost from the perspective of officebased physicians due to a lack of data on staff time requirements
and valuation of staff time. Hourly wage rates in office-based

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533
Table 5. Cost of CINV incurred by third party payers (sick funds) and patients, and indirect costsa
Type of cost

Mean cost per treatment cycle per patient in 2002,$

Cycles with CINV (n = 134)

All cycles (n = 208)

Direct cost incurred by third party payer

11.20 36.90 [0.00]

7.22 30.07 [0.00]

CINV-attributable outpatient physician visits

4.65 11.25 [0.00]

2.99 9.29 [0.00]

CINV-attributable (extended) hospitalizations

5.34 61.80 [0.00]

3.44 49.60 [0.00]

Ambulance transport

3.04 35.22 [0.00]

1.96 28.27 [0.00]

Subtotal: costs of treatment of CINV

24.23 119.59 [0.00]

15.61 96.56 [0.00]

Medication to prevent CINV (prophylaxis)c

45.37 65.39 [0.00]

33.05 57.07 [0.00]

Total: costs of prophylaxis plus treatment

69.60 135.18 [33.21]

48.66 113.01 [0.00]

Medication to treat CINVb

Direct out-of-pocket costs incurred by patients

1.46 7.06 [0.00]

0.94 5.71 [0.00]

Taxi/public transportation

0.79 2.36 [0.00]

0.51 1.93 [0.00]

Extra home help/childcare

2.39 13.27 [0.00]

1.54 10.65 [0.00]

Total

4.64 27.90 [0.00]

2.99 22.47 [0.00]

3.05 22.74 [0.00]

1.97 18.28 [0.00]

Indirect costs
Workdays losttotal cost per patient
Direct costthird party payer (cost of
prophylaxis plus treatment)

69.60 135.18 [33.21]

48.66 113.01 [0.00]

Direct costpatient

4.64 27.90 [0.00]

2.99 22.47 [0.00]

Indirect cost

3.05 22.74 [0.00]

1.97 18.28 [0.00]

Total

77.30 146.59 [36.14]

53.62 122.72 [0.00]

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.

settings are dependent on the income of individual office practices.

Hence, they are not publicly available and may vary considerably
across centers.
Even though we may have captured an almost complete spectrum
of costs directly attributable to CINV, we are also not presenting
cost data from a societal perspective. We recognise that this is a
shortcoming of our analysis [4], since resource allocation decisions
should ideally be made from a societal perspective [20]. However,
the complexity of the cost structure in Germany, which may result
in double counting of individual line items and a lack of data,
virtually preclude calculation of this perspective. For example,
data on the true cost per day in hospital or per outpatient visit have
not been published or otherwise available to us. Given these limitations, the best proxy estimate of societal cost of CINV is likely
obtained by adding the costs incurred by third party payers and
patients, and indirect costs. This yields a total cost estimate of
$53.62 per patient per treatment cycle (Table 5).
To provide further insight into the relative influence of different
patient or treatment characteristics on the overall cost of CINV,
we constructed several subgroups of patients. This analysis was

limited to patients treated in hospital settings from the providers

perspective. The rationale for excluding patients treated in physician
offices was the difference in cost structure between the settings,
and the fact that allocation of patients to the different settings was
non-random, and the lack of comparability of the groups with
regard to type of malignancy and chemotherapy (Table 1) would
have confounded subgroup analyses from the combined populations.
Not surprisingly, cisplatin-containing chemotherapies were
associated with higher average costs of prophylaxis and treatment
of CINV than non-cisplatin regimens (Table 7). Subgroup
analyses further show that overall cost of CINV was associated
with presence of vomiting, presence of delayed CINV, and inadequate prophylaxis for delayed CINV (as indicated by a lack of
adherence with ASCO guidelines for delayed CINV, although this
did not reach the level of significance; Table 7). These findings are
directly relevant to patient-management decisions, as they identify
subgroups of patients for whom improved CINV prophylaxis is
likely to result in the highest levels of cost savings or cost offset.

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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

1.32 6.17 [0.00]

All cycles (n = 137)

0.71 4.54 [0.00]

0.69 1.93 [0.00]

0.37 1.44 [0.00]

Staff time and material consumption associated

with managing episode of CINV

25.30 109.13 [0.00]

13.48 80.41 [0.00]

Subtotal

27.31 109.20 [0.00]

14.55 80.62 [0.00]

Medication to prevent CINV (prophylaxis)

17.38 9.73 [15.98]

17.25 9.52 [15.98]

Prophylactic drug administration devices and staff time

16.51 5.07 [20.60]

16.46 5.07 [20.60]

Subtotal

33.89 11.42 [36.13]

33.72 11.09 [36.58]

Total

61.20 109.68 [38.08]

48.27 81.33 [36.58]

Rescue-drug administration devices

How do our findings compare with results from similar studies?

We found two reports concerned with CINV-attributable costs in
Germany. Ihbe-Heffinger et al. [21] quantified the costs of drug
acquisition and administration associated with the control of
CINV from a hospital perspective. In their cohort of breast cancer
patients receiving moderately emetogenic chemotherapy, total
costs (comprising prophylaxis and treatment of CINV) ranged
from $35 to $73, depending on the type of antiemetic drugs used.
This is in good agreement with our data from the hospital treatment setting.
Herold and Hieke [5] compared the cost of toxicity of standard
chemotherapy given to patients with non-Hodgkins lymphoma in
several countries. In their retrospective analysis, the average cost
to third party payers for managing CINV in Germany was $358
per patient for a complete course of treatment, which typically
comprised six cycles of chemotherapy. Hence, average cost per
patient per cycle amounts to approximately $60, which is also in
line with our findings of $48.66 in a more heterogeneous patient
population.
It is difficult to compare our findings on costs of CINV with
other reports because published information is limited. To the best
of our knowledge, there is only one study that is similar in design
to ours [3], but it predates the availability of 5-HT3 receptor antagonists, and relates to the Canadian healthcare environment.
A number of methodological aspects of this study deserve discussion. Our study was prospective and was based on specifically
designed questionnaires; all data acquisition was performed or
monitored by experienced and trained personnel. These study features allowed us to capture cost items with a degree of accuracy
and completeness that may not usually be available from retrospective chart review or medical claims data.
This study was not restricted to a particular cancer type and we
have deliberately enrolled a heterogeneous group of cancer

patients with a variety of malignancies. Patients received a broad

range of chemotherapies, all of which are considered highly
emetogenic [1]. This is expected to make our results relevant for
extrapolation to most cancer patient populations on highly
emetogenic treatments.
Our study may have systematically underestimated the true cost
of CINV in at least two ways. Firstly, and as discussed above, the
results indicate that management of CINV may have been suboptimal, and improved management might result in cost savings
that are not apparent from our study, since we did not consider the
cost of chemotherapy administration. Stewart et al. [22] observed
retrospectively that the improved control of CINV by the introduction of 5-HT3 antagonists enabled the administration of larger
doses of chemotherapy in shorter periods of time. As a result,
some multi-day regimens were successfully converted to singleday regimens, and prolonged infusions given on an inpatient basis
were converted to relatively short outpatient infusions. Hence, our
study may have underestimated the resources wasted (i.e. not
saved) due to the continuing high rate of CINV. Conceivably,
more savings or cost offsets could be achieved by reducing the
frequency and severity of CINV, either by optimizing the management with existing medication or by use of novel antiemetic
agents with improved efficacy.
Secondly, we have not factored in less tangible and hidden
costs, such as unpaid family labor and time in caring for patients,
or patients inability to perform household work, which are often
ignored but may not be insignificant [23, 24].
Nevertheless, the present results document that 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. Our data indicate

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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

Emesis (any level)

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

Level of acute or delayed CINVb

Presence of delayed CINVc

Adherence to ASCO guidelines for

prophylaxis of delayed CINV

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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