Delayed Nausea and Vomiting Continue to Reduce Patients’
`Quality of Life After Highly and Moderately Emetogenic
`Chemotherapy Despite Antiemetic Treatment
`Brigitte Bloechl-Daum, Robert R. Deuson, Panagiotis Mavros, Mogens Hansen, and Jørn Herrstedt
`ABSTRACT
`Purpose
`Chemotherapy-induced nausea and vomiting (CINV) are major adverse effects of cancer chemo-
`therapy. We compared the impact of acute (during the first 24 hours postchemotherapy) and
`delayed (days 2 through 5 postchemotherapy) CINV on patients’ quality of life (QoL) after highly or
`moderately emetogenic chemotherapy (HEC and MEC, respectively).
`Patients and Methods
`This prospective, multicenter, multinational study was conducted in 14 medical practices on
`cancer patients undergoing either HEC or MEC treatment. Patients recorded episodes of nausea
`and vomiting in a diary. Patients completed the Functional Living Index-Emesis (FLIE) question-
`naire at baseline and on day 6.
`Results
`A total of 298 patients were assessable (67 HEC patients, 231 MEC patients). Emesis was
`reported by 36.4% of patients (13.2% acute, 32.5% delayed) and nausea by 59.7% (36.2% acute,
`54.3% delayed). HEC patients reported significantly lower mean FLIE total score than MEC
`patients (95.5 v 107.8 respectively; P /H11005.0049). Among all patients, the nausea score was
`significantly lower than
`the vomiting score (50.0 and 55.3, respectively; P /H11005.0097). Of the 173
`patients who experienced
`neither vomiting nor nausea during the first 24 hours postchemo-
`therapy, 22.9% reported an impact of CINV on daily life caused by delayed CINV.
`Conclusion
`CINV continues to adversely affect patients’ QoL despite antiemetic therapy even after treatment
`with only moderately emetogenic chemotherapy regimens, and even in the subgroup of patients
`who do not experience nausea and vomiting during the first 24 hours. On the basis of the FLIE
`results in this study, nausea had a stronger negative impact on patients’ daily lives than vomiting.
`J Clin Oncol 24:4472-4478. © 2006 by American Society of Clinical Oncology
`INTRODUCTION
`Chemotherapy-induced nausea and vomiting (CINV)
`remain major adverse effects of cancer chemothera-
`py.
`1 Antiemetic treatments, including serotonin
`(5-HT3) receptor antagonists and corticosteroids,
`have been instrumental in improving the control of
`vomiting among patients receiving chemothera-
`py.
`2,3 However, recent studies have demonstrated
`the need for improved therapeutic intervention in a
`number of areas.
`4 For example, Roscoe et al 5 report
`that after the introduction of 5-HT 3 receptor antag-
`onists, the incidence of nausea may actually have
`risen despite the reduction in the incidence of
`vomiting. Furthermore, antiemetic treatments
`have been less effective in improving delayed nau-
`sea and vomiting than acute nausea and vomit-
`ing.
`6 Two meta-analyses of clinical trials have
`shown that 5-HT 3 receptor antagonists with or
`without corticosteroids are not effective against
`delayed emesis and nausea. 7,8
`The lack of adequate CINV control may be
`partly attributed to the fact that antiemetic treat-
`ment regimens are guided by risk factors, including
`level of emetogenicity of chemotherapeutic agents.
`9
`Emetic risk categories are based on experience rather
`than specific data, and the categories refer to acute
`emesis only.
`6,10 Moreover, the neuropharmaco-
`logic mechanism of delayed CINV (/H11022 24 hours
`postchemotherapy) is not well understood, and
`prevention of delayed CINV has largely been
`based on empiric results.
`CINV adversely impact patients’ quality of
`life
`11-14 From a list of chemotherapy-related adverse
`effects, patients rated nausea as their first and vom-
`iting as their third most feared symptom.
`15 In a
`From the Department of Clinical Phar-
`macology, Medical University of Vienna,
`Vienna, Austria; Outcomes Research,
`Merck & Co, Whitehouse Station, NJ;
`Department of Internal Medicine F,
`Hillerød Hospital, Hillerød; and the
`Department of Oncology, Copenhagen
`University Hospital Herlev, Herlev,
`Denmark.
`Submitted January 8, 2006; accepted
`July 19, 2006.
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`Address reprint requests to Brigitte
`Bloechl-Daum, MD, Department of Clinical
`Pharmacology, Medical University of
`Vienna, Allgemeines Krankenhaus,
`Waehringer Guertel 18-20, A-1090 Vienna,
`Austria; e-mail: brigitte.bloechl-daum@
`meduniwien.ac.at.
`© 2006 by American Society of Clinical
`Oncology
`0732-183X/06/2427-4472/$20.00
`DOI: 10.1200/JCO.2006.05.6382
`JOURNAL OF CLINICAL ONCOLOGY
`ORIGINAL REPORT
`VOLUME 24 /H18528NUMBER 27 /H18528SEPTEMBER 20 2006
`4472
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`HELSINN EXHIBIT 2075
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
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`recent study, ovarian cancer patients included complete to almost
`complete
`control from CINV among the most favorable health states,
`just below perfect health and clinical remission. 16
`Against this background, the Anti Nausea Chemotherapy Regis-
`try (ANCHOR) study was designed to address two issues; (i) to pro-
`spectively compare, under current practice patterns, the incidence of
`acute and delayed nausea and emesis after highly and moderately
`emetogenic chemotherapy (HEC and MEC, respectively), and (ii) to
`assess the impact of acute and delayed nausea and vomiting after HEC
`and MEC on patients’ quality of life (QoL). The Functional Living
`Index-Emesis (FLIE), a validated nausea- and vomiting-specific
`patient-reported outcome measure was used to evaluate the impact of
`CINV on patients’ daily lives.
`17,18 Results on the incidence of CINV
`after HEC or MEC are reported elsewhere. 19 In the following, we
`address the impact of CINV on patients’ daily life.
`PATIENTS AND METHODS
`Study Design and Setting
`This prospective, multicenter, observational study was conducted in 14
`medical practices in Denmark, France, Italy, Germany, the United Kingdom,
`and the United States during 2001 to 2002. 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.
`Patient Selection Criteria
`Patients were eligible for inclusion if they were adults (/H1102218 years of age),
`never had chemotherapy before study entry (chemotherapy naı ¨ve), and were
`scheduled for treatment with either HEC (ie, at least one chemotherapeutic
`agent of Hesketh Level 5 emetic potential; eg, /H1102250 mg/m
`2 of cisplatin or
`/H110221,500 mg/m2 of cyclophosphamide) or (ie, at least one chemotherapeutic
`agent of Hesketh Levels 3 or 4 emetic potential; eg, /H1102220 mg/m2 of doxorubicin
`or /H110211,500 mg/m2 of cyclophosphamide).10
`Patients were not eligible for participation in the study if they were
`scheduled to receive multiple-day chemotherapy, or if they had vomited dur-
`ing the 24-hour period preceding chemotherapy administration.
`The protocol was approved by the ethics committees/institutional
`review boards according to the requirements in each participating country.
`Written and signed informed consent was obtained from all patients before
`study entry.
`Data Collection
`Patients who agreed to participate received a diary covering the 24 hours
`before chemotherapy, the day of chemotherapy administration (day 1) and the
`following 4 days (day 2 through 5). Patients were instructed to use the diary
`every day to record each emetic episode and to provide daily nausea assess-
`ments using a 100-mm visual analog scale (VAS) to rate the severity of nausea
`experienced during the preceding 24 hours. Patients also recorded all rescue
`antiemetic medications, which were taken in addition to what was prescribed
`at baseline to prevent nausea and vomiting. No nausea was defined as a VAS
`less than 5 mm on the 100-mm scale. A patient was considered to have had
`acute nausea or acute emesis if nausea (VAS /H113505mm) or at least one episode of
`vomiting was reported during the first 24 hours after start of chemotherapy.
`Any episodes of nausea and/or vomiting thereafter up to 5 days after chemo-
`therapy was considered delayed.
`6
`In addition, patients were asked to complete the FLIE, a self-
`administered questionnaire used to evaluate the impact of CINV on patients’
`daily lives. The development of the FLIE has been described previously.
`17,18
`The FLIE instrument was modeled after the Functional Living Index-Cancer, a
`patient-completed multidimensional quality of life instrument. The FLIE is a
`validated nausea- and vomiting-specific patient-reported outcome instru-
`ment composed of two domains (vomiting and nausea) with nine identical
`items in each domain. The FLIE-item score was assessed at baseline (preche-
`motherapy) and on the morning of day 6 postchemotherapy. The first item in
`each domain asked the patient to rate how much nausea and vomiting he or
`she had experienced during the previous 5 days. The remaining eight items
`covered different sections influencing the patient’s quality of daily life (ie,
`“recreation or leisure activities,” “make meal/do tasks,” “ability to enjoy meal,”
`“enjoy drinking fluids,” “see family/ friends,” “daily functioning,” “personal
`hardship,” “hardship on others”). The FLIE-score was determined by sum-
`ming the responses to the 18 questions on a seven-point analog scale. There-
`fore, the range of total scores possible is between 18 (all one responses on each
`scale) and 126 (all seven responses on each scale). A higher score corresponds
`to a higher QoL or less impact of CINV on daily life.
`20
`No or minimal impact on daily life (NIDL) was defined as an average
`FLIE item score of more than 6 on the seven-point continuous visual analog
`scale or a total FLIE-Score of more than 108.
`Data Analysis
`Descriptive statistics were used to summarize patient demographics and
`survey responses. The t test for paired and unpaired observations was used as
`appropriate for comparison of group means. Differences in the proportion of
`patients that reported NIDL between MEC and HEC treated patients were
`analyzed using
`/H92732 tests (Fisher’s exact test).
`RESULTS
`Description of Patient Sample
`A total of 322 patients from 14 centers were enrolled in the study
`(patient disposition is shown in Fig 1). One patient was lost to follow-
`up, one patient died during the observation period; no questionnaires
`could be obtained from six patients. Questionnaires from 16 further
`patients had to be excluded from the analysis because of incomplete
`data or protocol violations. Hence, 298 patients were assessable: 85
`were male, 213 were female, and the mean age was 55.5 years (standard
`deviation, 12.1 years). The most frequent diagnoses were breast
`(49.3%) and lung (17.8%) cancers. Sixty-seven (22.5%) patients re-
`ceived HEC; of these, 61 (91%) received cisplatin, and six (9%) dacar-
`bazine. Two hundred thirty-one patients(77.5%) received MEC; of
`these 163 (70%) received regimens containing cyclophosphamide,
`doxorubicin, and/or epirubicin; 59 (25%) received carboplatin-
`containing regimens; and nine (5%) received other regimens.
`19
`Antiemetic therapy consistent with the guidelines6,21,22 in force at
`the time and place of the study was used in most of the patients, and
`has been described in detail previously.
`19 Briefly, 282 patients
`(96.6%) received 5-HT 3 receptor antagonists, and 227 (77.7%)
`
`
`314 patients
`completed the
`study
`322 patients
`enrolled
`8 patients dropped out
`Data from 16 patients
`excluded from analyses
`due to incomplete data
`or protocol violations
`298 patients
`included in
`analyses
`6 patients: no
`questionnaire
`could be obtained
`1 patient died
`1 patient: lost
`to follow-up
`Fig 1. Patient disposition chart.
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`received corticosteroids. Two hundred fifty patients (85.6%) received
`prophylaxis
`for delayed CINV (/H1102224 hours postchemotherapy). The
`most common duration of 5-HT 3 receptor antagonist therapy and
`corticosteroid therapy was 3 days, with 71% of patients receiving
`5-HT3 receptor antagonists and 55% of patients receiving a cortico-
`steroid for at least that long.
`Frequency of Emetic Episodes and Nausea During the
`5-Day Period After Chemotherapy
`Results on the incidence of acute and delayed CINV across chem-
`otherapy treatment groups are reported elsewhere. 19 In summary,
`13.2% of the patients reported emetic episodes, and 36.2% nausea,
`during the 24-hour period after administration of chemotherapy,
`whereas delayed emesis was reported by 32.5% of the patients and
`delayed nausea by 54.3%.
`The daily incidence of emesis and its prevalence are reported in
`Table 1 and Figure 2. The prevalence of acute emesis was similar
`between HEC- and MEC-treated patients (11.9% and 13.2%, respec-
`tively), but HEC treated patients were significantly more likely to
`report delayed emesis than MEC treated patients (P /H11021.05). On aver-
`age, HEC treated patients reported more emetic episodes per day per
`patient than MEC treated patients for both the acute (3.1 v 2.5, respec-
`tively) and the delayed phase (1.4 v 1.2, respectively).
`The daily incidence and severity of nausea are summarized in
`Table 2 and Figure 2. The rate of nausea plateaued between days 2 and
`3. There were no significant differences in the rate of acute and delayed
`nausea between HEC- and MEC-treated patients, but HEC-treated
`patients reported greater nausea severity especially in days 2 through 5,
`as indicated by the mean VAS score during each period (Table 2).
`Impact of Nausea and Vomiting on Patients’
`Daily Life
`At baseline, 95.3% of the patients reported NIDL with an average
`total FLIE score of 122.9. There was no difference between patients
`scheduled for HEC (93.9% NIDL, total FLIE score 123.1) and MEC
`(95.6% NIDL, total FLIE score 122.9) at baseline.
`Results from all items of the FLIE obtained on day 6 are summa-
`rized in Table 3. On day 6 postchemotherapy, the mean total FLIE
`score was 105.4; however, 61.0% of all patients reported that CINV
`had no or minimal impact on their daily life (ie, total FLIE score
`/H11022108). The average FLIE score indicates that patients receiving HEC
`experienced a greater impact of CINV on their daily life than patients
`receiving MEC (95.5 v 107.8, respectively P /H11005.0049). Significantly
`fewer HEC than MEC patients (47.2% and 64.5%, respectively) re-
`ported NIDL (P /H11005.0272).
`Among all patients, the mean FLIE nausea domain score on day 6
`was 50.0 (44.7 for HEC and 51.4 for MEC; P /H11005.0024), whereas the
`mean FLIE vomiting domain score was 55.3 (50.3 for HEC and 56.5
`for MEC; P /H11005.0097), indicating that nausea had a stronger impact on
`daily life than vomiting (Table 3). This is also reflected by the NIDL
`data because only 53.1% of patients reported NIDL for nausea, com-
`pared with 73.4% with NIDL for vomiting (Fig 3). The greater impact
`of nausea on daily life is also emphasized by results from individual
`FLIE items shown in Figure 4: The change from baseline to day 6 was
`more pronounced for all individual nausea domain items than for the
`corresponding vomiting domain items.
`Impact of Acute and Delayed CINV on Patients’
`Daily Life
`Table 4 reports the proportion of patients reporting NIDL for
`those with acute or delayed vomiting or nausea. On the basis of the
`total FLIE score, the observed trend is that patients with neither acute
`Table 1. Frequency of Emetic Episodes During the 5-Day Period After Chemotherapy
`Days After Chemotherapy
`All
`Patients HEC Patients MEC Patients
`Patients
`Episodes
`(No.)
`Patients
`Episodes
`(No.)
`Patients
`Episodes
`(No.)
`Missing
`Values
`Total
`No. %
`Missing
`Values
`Total
`No. %
`Missing
`Values
`Total
`No. %
`1 (acute emesis) 38 287 13.2 99 7 59 11.9 22 30 226 13.2 74
`2
`48 286 16.8 122 16 58 27.6 45 31 226 13.7 75
`3 46 286 16.1 109 19 58 32.8 48 26 226 11.5 60
`4
`49 286 17.1 89 14 58 24.1 28 34 226 15.0 57
`5 35 286 12.2 58 15 58 25.9 24 19 226 8.4 31
`2-5
`(delayed emesis) 93 286 32.5 378 29 58 50.0 167 63 226 27.9 297
`NOTE. A total of 298 patients were enrolled. This includes three patients for whom there was no sufficient information to classify them as HEC or MEC. The smaller
`number
`of patients reporting emesis reflects missing values.
`Abbreviations: HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy.
`Fig 2. Frequency of nausea and vomiting during the 5-day period after
`chemotherapy. HEC, highly emetogenic chemotherapy; MEC, moderately eme-
`togenic chemotherapy.
`Bloechl-Daum et al
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`nor delayed nausea or vomiting are more likely to report NIDL than
`patients
`who reported both acute and delayed nausea or vomiting
`(78.3% v 20.8% for vomiting, 94.4 for v 26.5 for nausea). On average,
`patients with neither acute nor delayed nausea or vomiting report higher
`FLIE total scores than patients with both acute and delayed nausea or
`vomiting (115.9v 72.1 for vomiting, 121.9 forv 86.2 for nausea).
`Data in Table 4 show that only 155 (66.8%) of 232 patients
`without acute vomiting reported NIDL on day 6. Similarly, among the
`168 patients who experienced no acute nausea, 129 (76.7%) reported
`NIDL on day 6.
`DISCUSSION
`It may seem self-evident that nausea and vomiting after chemotherapy
`have
`a negative impact on patients’ health-related QoL, but there are
`Table 2. Nausea Assessment–Incidence and Severity
`Day After Chemotherapy
`All
`Patients HEC Patients MEC Patients
`Patients
`Nausea VAS
`(mean /H11006SD)
`Patients
`Nausea VAS
`(mean /H11006SD)
`Patients
`Nausea VAS
`(mean /H11006SD)
`Missing
`Values
`Total
`No. %
`Missing
`Values
`Total
`No. %
`Missing
`Values
`Total
`No. %
`Prechemotherapy period 15 293 5.1 1.1 /H110064.5 6 63 9.5 1.8 /H110065.8 8 227 3.5 0.8 /H110063.8
`1 (acute nausea) 106 293 36.2 12.8 /H1100623.2 21 63 33.3 13.1 /H1100624.1 83 227 36.6 12.4 /H1100622.6
`2 119 293 40.6 14.6 /H1100624.2 32 63 50.8 25.8 /H1100634.1 85 227 37.4 11.3 /H1100619.7
`3 121 293 41.3 15.0 /H1100625.0 34 63 54.0 25.7 /H1100631.9 85 227 31.9 11.9 /H1100621.8
`4 108 293 36.9 11.1 /H1100619.7 29 63 46.0 18.0 /H1100625.8 77 227 33.9 9.0 /H1100616.9
`5 93 293 31.7 8.7 /H1100617.8 25 63 39.7 15.9 /H1100625.7 66 227 29.1 6.4 /H1100613.9
`2-5 (delayed nausea) 159 293 54.3 38 63 60.3 119 227 52.4
`NOTE. The measurements are based on a 100-mm VAS for nausea. No nausea was defined as nausea VAS score /H110215 mm. A total of 298 patients were
`enrolled. These data includes three patients for whom there was no sufficient information to classify them as HEC or MEC. The smaller number of patients reporting
`emesis reflects missing values.
`Abbreviations: HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy; VAS, Visual Analog Scale; SD, standard deviation.
`Table 3. QoL Assessment and Test of Differences in QoL by Treatment Type Based on Responses to the FLIE Questionnaire on Day 6 Postchemotherapy
`FLIE Item
`All
`Patients HEC Patients MEC Patients
`FLIE
`Score
`P /H11569
`NIDL
`P †
`No. With NIDL
`FLIE
`Score
`No. With NIDL
`FLIE
`Score
`No. With NIDL
`FLIE
`Score
`Missing
`Values
`Total
`No. %
`Missing
`Values
`Total
`No. %
`Missing
`Values
`Total
`No. %
`FLIE total score 163 267 61.0 105.39 25 53 47.2 95.50 138 214 64.5 107.83 .0049 .0272
`Nausea
`domain total score 144 271 53.1 50.03 20 55 36.4 44.74 124 216 57.4 51.37 .0024 .0063
`“Had nausea” 149 271 55.0 5.57 21 55 38.2 4.96 128 216 59.3 5.72 .0029 .0062
`“Recreation or leisure
`activities”
`166 271 62.3 5.58 28 55 50.9 5.17 138 216 63.9 5.69 .0740 .0889
`“Make meal/do tasks” 159 270 58.9 5.42 28 55 50.9 5.14 131 215 60.9 5.50 .2308 .2192
`“Ability to enjoy meal” 148 271 54.6 5.31 21 55 38.2 4.40 127 216 58.8 5.54 .0014 .0095
`“Enjoy drinking fluids” 171 271 63.1 5.69 29 55 52.7 5.02 142 216 65.7 5.86 .0098 .0857
`“See family/friends” 170 269 63.2 5.63 25 54 46.3 4.96 145 215 67.4 5.80 .0036 .0069
`“Daily functioning” 155 269 57.6 5.49 26 54 48.1 5.09 129 215 60.0 5.59 .0842 .1255
`“Personal hardship” 150 269 55.8 5.48 23 54 42.6 4.86 127 215 59.1 5.64 .0071 .0326
`“Hardship on others” 178 269 66.2 5.89 28 54 51.9 5.25 150 215 69.8 6.05 .0094 .0159
`Vomiting domain total score 196 267 73.4 55.26 32 53 60.4 50.31 164 214 76.6 56.49 .0097 .0233
`“Had
`nausea” 210 268 78.4 6.29 34 54 63.0 5.67 176 214 82.2 6.45 .0071 .0049
`“Recreation or leisure
`activities”
`204 267 76.4 5.97 36 54 66.7 5.60 168 213 78.9 6.06 .1168 .0725
`“Make meal/do tasks” 210 267 78.7 6.18 35 53 66.0 5.55 175 214 81.8 6.34 .0153 .0155
`“Ability to enjoy meal” 210 267 78.7 6.18 33 53 62.3 5.51 177 214 82.7 6.35 .0089 .0023
`“Enjoy drinking fluids” 214 267 80.1 6.28 33 53 62.3 5.57 181 214 84.6 6.45 .0056 .0008
`“See family/friends” 207 265 78.1 6.07 37 53 69.8 5.71 170 212 80.2 6.16 .1091 .1360
`“Daily functioning” 213 265 80.4 6.28 35 53 66.0 5.83 178 212 84.0 6.39 .0430 .0061
`“Personal hardship” 203 265 76.6 6.16 31 53 58.5 5.44 172 212 81.1 6.35 .0041 .0009
`“Hardship on others” 190 265 71.7 5.81 31 53 58.5 5.47 159 212 75.0 5.90 .1795 .0258
`NOTE. A total of 298 patients were enrolled. Smaller numbers are due to individual missing values from some patients.
`Abbreviations:
`QoL, quality of life; HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy; FLIE, Functional Living Index-Emesis
`questionnaire; NIDL, average FLIE item score of /H110226 on the seven-point scale.
`/H11569Based on t tests of the hypothesis that the mean scores of the FLIE items between MEC and HEC patients are not different.
`†Based on /H92732 tests of the hypothesis of no association between treatment type (MEC versus HEC) and effect on daily living measured by NIDL.
`Delayed Nausea and Vomiting Reduce QoL
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`little data from prospective clinical trials to demonstrate and quanti-
`tatively
`assess this adverse effect of treatment.20 Moreover, most stud-
`ies of the QoL effects of nausea and vomiting are characterized by
`narrow patient selection criteria and are limited to well-defined chem-
`otherapy regimens. Hence, it is not known to what extent the nausea-
`and vomiting-induced deterioration of QoL differs after chemother-
`apy regimens of different levels of emetogenicity. However, data on
`QoL deterioration would be useful to inform the choice of preven-
`tive antiemetic regimens. We set out to directly compare the inci-
`dence and QoL impact of nausea and vomiting after HEC and MEC
`in a representative sample of oncology patients under patterns of
`daily clinical practice.
`Incidence rates of CINV in our patients are in agreement with
`results from previous, similar studies.
`23,24 The central findings from
`this study were that both HEC and MEC patients reported delayed
`nausea and vomiting more often than acute nausea and vomiting.
`Although delayed emesis occurred in almost twice as many HEC as
`MEC patients, the rate of delayed nausea was unexpectedly similar
`after HEC and MEC treatment (60.3% v 52.4%, respectively). This
`indicates that level of emetogenicity may not be as strong a predictor of
`delayed nausea as might be assumed. The potential clinical rele-
`vance of this observation is emphasized by the finding that nausea
`had a stronger negative impact on QoL than vomiting. This was
`consistent across all items of the FLIE score (Fig 3), and more
`patients experienced an impact on daily life from nausea than from
`vomiting (Table 3; Fig 2). This is in concordance with the finding that
`5-HT
`3 receptor antagonists, such as ondansetron and granisetron,
`have been successful in preventing vomiting, but less effective in the
`prevention of nausea.
`25
`Both absolute FLIE scores and the proportions of patients report-
`ing NIDL were significantly different between HEC- and MEC-treated
`groups, demonstrating that HEC patients suffered more of an impact
`Fig 4. Impact of nausea and vomiting on
`patients’ quality of life: mean change in
`Functional Living Index-Emesis (FLIE)
`items score from baseline. A greater neg-
`ative change means a greater impact of
`the symptom on that aspect of quality of
`life. Results indicate that nausea had a
`stronger negative impact on all FLIE items
`than vomiting.
`Fig 3. Proportions of patients reporting “no impact on daily life” (NIDL) for
`nausea and vomiting domains on day 6 postchemotherapy, by treatment type.
`Results indicate that vomiting had an impact on fewer patients’ quality of life than
`nausea. HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic
`chemotherapy.
`Table 4. Percentage of Patients Reporting NIDL and Mean and Median
`FLIE Total Score by Acute and/or Delayed CINV Based on Responses to the
`FLIE Questionnaire on Day 6 Postchemotherapy
`Occurrence of CINV
`(acute,
`delayed)
`No. of
`Patients
`Patients
`Reporting
`NIDL Total FLIE Score
`% No. Mean Median
`Vomiting
`(/H11001,/H11001)
`24 20.83 5 72.10 67.23
`(/H11001, –) 10 30.00 3 94.61 102.51
`(–, /H11001) 57 31.58 18 89.65 84.84
`(–, –) 175 78.29 137 115.94 121.44
`Nausea
`(/H11001,/H11001) 83 26.51 22 86.22 87.96
`(/H11001, –) 15 80.00 12 114.79 117.36
`(–, /H11001) 61 45.90 28 100.80 104.28
`(–, –) 107 94.39 101 121.94 125.94
`NOTE. Ordered pairs of /H11001and – indicate the presence and absence
`respectively of the relevant condition. The first element of an ordered pair
`refers to the acute phase and the second to the delayed phase. NIDL is based
`on FLIE total score.
`Abbreviations: NIDL, no or minimal impact on daily life; CINV, chemotherapy-
`induced nausea and vomiting; FLIE, Functional Living Index-Emesis questionnaire.
`Bloechl-Daum et al
`4476 JOURNAL
`OF CLINICAL ONCOLOGY
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`on QoL. This finding, although not unexpected, has not, to our
`knowledge,
`been described previously. Nonetheless, our data (Table
`3) indicate that the percentage of MEC patients who experienced an
`impact on daily living was as high as 35.5 for the FLIE total score and
`42.6 for the nausea domain score (corresponding to 64.5% and 57.4%
`NIDL, respectively). This indicates that nearly one in two patients
`suffered an impact on daily life, primarily from nausea, even though
`they received only moderately emetogenic regimens. Our findings
`highlight the need for adequate prevention of CINV, even after MEC.
`Considering that most of our MEC patients received antiemetic treat-
`ment consistent with guidelines relevant at the time of this study, this
`also supports the notion that management of MEC patients may not
`have been adequately addressed, even in treatment guidelines for
`prevention of CINV.
`24
`Results from this study may also be applied to assess the useful-
`ness of acute CINV as a predictor of impact on QoL: It could be argued
`that the subgroup of patients who do not experience acute CINV are
`unlikely to suffer a negative impact on QoL and, hence, might be
`accorded lower priority for prevention of delayed CINV. This is not
`supported by our findings, as shown in Table 4. A considerable num-
`ber of patients who had reported no episodes of nausea or vomiting
`during the first 24 hours after treatment suffered an impact on QoL
`during the postchemotherapy period. Results shown in Table 4 also
`indicate that patients who experienced delayed but not acute nausea
`were more likely to report an impact on daily living than patients who
`experienced only acute nausea. The corresponding FLIE scores indi-
`cate that delayed CINV has a more severe impact on daily living than
`acute CINV. This may be attributed to the greater length of time over
`which delayed CINV could be experienced.
`Several methodologic aspects of our study deserve discussion.
`Our prospective investigation was based on the FLIE score, a validated
`instrument with questions specifically addressing the impact of CINV
`on the physical abilities, social and emotional function, and ability to
`enjoy meals.
`20 Patient management and data acquisition were per-
`formed by experienced centers and personnel. The study was not
`restricted to a particular cancer type, and we have deliberately enrolled
`a heterogeneous group of cancer patients receiving a broad range of
`chemotherapies. This is expected to make our results relevant for
`extrapolation to most cancer patient populations on highly or mod-
`erately emetogenic treatments.
`The importance of the time of administration after chemother-
`apy of the QoL assessment has been addressed previously. Because
`CINV is most intense during the first 3 days after chemotherapy, it is
`critical that these days be included in the observation period. More-
`over, the observation period must not be overly long to minimize
`recall bias that may result in loss of assay sensitivity.
`20,26 In this study,
`we administered the FLIE questionnaire in the morning of day 6, a
`period that was judged to be adequate on the basis of results from a
`previous study on the timing of QoL assessment of CINV
`26 and
`further validated in a clinical trial sample. 18 Furthermore, the 5-day
`period is expected to include most CINV-related events without a
`relevant level of recall bias.
`Only treatment-naı ¨ve patients were enrolled in this study. This
`may limit extrapolation of our findings to the first cycle of chemother-
`apy because previous experience has shown that the antiemetic effect
`decreases during subsequent cycles.
`27 Hence, results of our study may
`underestimate the overall impact of CINV on patient’s daily life dur-
`ing subsequent cycles of their chemotherapy.
`Guidelines on antiemetic prophylaxis for patients undergoing
`HEC have been amended since the time when this study was conduct-
`ed.
`28 For these patients, a three-drug combination, including a
`neurokinin-1 receptor antagonist, may now offer better protection,
`but for MEC patients current guidelines are still in line with the
`practice pattern in our study.
`29
`In conclusion, our findings support the notion that CINV con-
`tinues to adversely affect patients’ QoL, even after treatment with
`moderately emetogenic regimens, and even in the subgroup of pa-
`tients who do not experience nausea and vomiting during the first 24
`hours. Nausea has a stronger negative impact on QoL than vomiting.
`Patients in this study were included at the first cycle of chemother-
`apy. It is well known that the antiemetic effect of a serotonin
`receptor antagonist and a corticosteroid declines through subse-
`quent cycles of HEC
`30 or MEC. 31 This emphasizes the need for new
`and potent antiemetics.
`Recently, the American Society of Clinical Oncology has updated
`its guidelines for antiemetic use in oncology. The updated guidelines
`state that before patients are receiving chemotherapy of high emetic
`risk (eg, an anthracycline and cyclophosphamide), a three-drug regi-
`men of a 5-HT
`3 serotonin receptor antagonist, dexamethasone, and
`aprepitant is recommended.32 The two-drug combination of dexa-
`methasone and aprepitant is recommended for the prevention of
`delayed emesis in patients receiving cisplatin or other agents of
`high emetogenicity. Future studies will show whether this updated
`regimen will translate into an improved QoL for patients under-
`going chemotherapy.
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