Received: 1 January 2003Accepted: 24 April 2003Published online: 3 July 2003© Springer-Verlag 2003

Supported in part by Grants-in-aid for Cancer Research from the Ministry ofHealth and Welfare and from the Second-term Comprehensive 10-year Strategy for Cancer Control.

Abstract The prevention of post-chemotherapy symptoms such as de-layed emesis, anorexia, and fatigueinduced by irinotecan has not beenstudied. We compared the effects ofdexamethasone (Dex) with those of aplacebo on these symptoms in a ran-domized study. Seventy patientsscheduled to receive irinotecan che-motherapy were enrolled in the studyand randomly divided into a treat-ment or a placebo group. In the treat-ment group, 8 mg of Dex were ad-ministered on days 2–4 after the startof chemotherapy. All patients in bothgroups received Dex and granisetronfor prophylaxis against acute emesison day 1. We evaluated 68 patients(35 receiving Dex, 33 receiving theplacebo). Although delayed emesiswas completely prevented in most ofpatients in both groups (Dex, 82.9%;placebo, 78.8%), anorexia and fa-tigue were more completely prevent-ed in those in the Dex group (Dex,

62.9% and 77.1%, placebo, 39.4%and 57.6%, respectively). The effectof Dex on improving simultaneousprophylaxis against all three symp-toms was almost significant (Dex,60.0%; placebo, 36.4%; P=0.058).The safety profiles of the two groupswere not discernibly different. Theseresults suggest that treatment withDex may be beneficial to reducepost-chemotherapy symptoms in-duced by irinotecan, specifically an-orexia and fatigue, with acceptabletoxicities.

Keywords Irinotecan · Dexamethasone · Delayed emesis ·Anorexia · Fatigue

Support Care Cancer (2003) 11:528–532DOI 10.1007/s00520-003-0488-y O R I G I N A L A RT I C L E

Akira InoueYasuhide YamadaYasuhiro MatsumuraYasuhiro ShimadaKei MuroMasahiro GotohTetsuya HamaguchiToshiro MizunoKuniaki Shirao

Randomized study of dexamethasone treatment for delayed emesis, anorexia and fatigue induced by irinotecan

Introduction

Irinotecan (CPT-11) is a potent inhibitor of topoisome-rase I, a nuclear enzyme involved in the unwinding ofDNA during replication. This drug has improved the re-sponse rate and survival of metastatic colorectal cancerpatients when used in combined chemotherapy regimensas a first-line treatment or alone as a second-line chemo-therapy treatment [4, 12, 13]. CPT-11 is also an activeagent against gastric cancer [2], lung cancer, and othermalignancies [6, 8, 10]. The most common nonhemato-logical toxicity induced by CPT-11 is diarrhea, and ame-

liorative treatments for diarrhea have been extensivelyinvestigated [1, 9, 16]. However, prophylaxis for delayedemesis, anorexia, and fatigue, which are also frequentsymptoms of toxicity that appear in patients treated withCPT-11, has been neglected, despite its clinical impor-tance. For example, the incidences of grade 3/4 anorexiaand fatigue were reported to be 5% and 13–15% in pre-vious studies [4, 13]. According to the drug informationof irinotecan opened by the Organization for Pharmaceu-tical Safety and Research (OPSR) in Japan, irinotecan-induced anorexia (grade 1–4) was observed in 74.1% ofall patients who enrolled in clinical trials before its ap-

A. Inoue (✉)Department of Respiratory Oncology and Molecular Medicine,Institute of Development, Aging, and Cancer, Tohoku University,4-1 Seiryomachi Aobaku, 980-8575 Sendai, Japane-mail: akinoue@idac.tohoku.ac.jpTel.: +81-22-7178539Fax: +81-22-7178549

Y. Yamada · Y. Matsumura · Y. ShimadaK. Muro · M. Gotoh · T. HamaguchiT. Mizuno · K. ShiraoDepartment of Medical Oncology,National Cancer Center Hospital,5-1-1 Tsukiji Chuo-ku, 104-0045 Tokyo, Japan

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proval in Japan [21]. Such symptoms, if mild or moder-ate, must be controlled to prevent the treatment regimentfrom being disrupted. However, a standard treatment forthese symptoms is not available.

We have observed that in some patients treated withCPT-11, severe delayed emesis, anorexia, or fatigue im-proved after administration of dexamethasone (Dex).Dex is well recognized as an important antiemetic agent[5, 17]. However, its efficacy for delayed emesis, an-orexia, and fatigue induced by CPT-11 has not been stud-ied. Thus, we conducted a randomized study comparinga placebo with Dex for the management of CPT-11-in-duced delayed emesis, anorexia, and fatigue.

Patients and methods

Patients

Patients with advanced gastric or colorectal cancer scheduled toreceive CPT-11-containing regimens for the first time as a second-line chemotherapy treatment were enrolled in this study. Patientsscheduled to receive cisplatin (CDDP) combined with CPT-11were excluded. The criteria for exclusion before randomizationwere the presence of emesis (nausea or vomiting), anorexia, or fa-tigue of any grade by using the National Cancer Institute CommonToxicity Criteria (NCI-CTC); severe concurrent illnesses otherthan neoplasia; disease complication-induced vomiting (e.g., gas-trointestinal obstruction); CNS metastasis; contraindication to Dexand CPT-11 administration; concurrent therapy with corticoste-roids; concurrent radiation therapy; and pregnancy.

Our study was approved by the local ethics committee of theNational Cancer Center Hospital (NCCH); all patients gave theirwritten informed consent.

Drug administration

This study was conducted at a single institute (NCCH), and ran-domization was performed using the envelope method. The studysubjects were randomly placed in either the Dex group (8 mg/dayintravenously on days 2–4), or the placebo group (normal salineintravenously on days 2–4). Patients in both groups receivedgranisetron (3 mg) and Dex (8 mg) intravenously on day 1 to pre-vent CPT-11-induced acute emesis. No other treatment for emesis,anorexia, or fatigue was permitted unless at least one episode ofgrade 1 emesis, grade 2 anorexia, or grade 2 fatigue was observed.If patients experienced above-mentioned toxicities, appropriatemedications were permitted.

The chemotherapy regimens used in this study were biweeklyCPT-11 (150 mg/m2) alone or biweekly CPT-11 (150 mg/m2) withmitomycin-C (5 mg/m2) regimens that were investigated in otherclinical trials for metastatic colon cancer and advanced gastriccancer conducted at our hospital during the same period. Treat-ment was continued until one of the following criteria occurred:disease progression, unacceptable adverse effects, or the with-drawal of patient consent. Antiemetic treatment after the study pe-riod was provided at the discretion of the patient’s physician.

Treatment evaluation

The details of emesis, anorexia, fatigue, and other toxicities afterCPT-11 administration were recorded daily for 6 days, based on theNCI-CTC. Assessment during the study period was completed inthe hospital by the attending physician who did not know whetherthe patient was receiving Dex or the placebo. Acute emesis (nausea

or vomiting occurring within the first 24 h after chemotherapy) anddelayed emesis (nausea or vomiting occurring more than 24 h afterchemotherapy) were evaluated separately. In addition, patientswere instructed to record their subjective symptoms of emesis, an-orexia, and fatigue using questionnaires (we did not perform thevalidation study of the questionnaires) during the first 6 days of thetreatment protocol. Patients could select one of 11 ratings (0 nosymptoms–10 worst) for each symptom; each patient completed aquestionnaire just before treatment, on day 2 (for the acute emesis),and on day 6, recording the worst rating experienced during eachperiod. All patients stayed in the hospital until at least day 6 of thetreatment protocol. Postprotocol evaluations for other toxicities andfurther treatment were continued on an outpatient basis.

Statistical analysis

The primary endpoint of this study was the percentage of patients ex-periencing complete protection from delayed emesis, anorexia, andfatigue by referring to the previous antiemetic studies [17]. Completeprotection was defined as the absence of any toxicity of more thangrade 1 toxicity, as evaluated by a physician during the study period(days 1–6). The secondary endpoints were the prevention of delayedemesis, anorexia, and fatigue as evaluated by the patient, and the ab-sence of other adverse events. Thirty-one patients were needed ineach group to detect a 20% improvement in the percentage of pa-tients experiencing complete protection from delayed emesis (90%of patients receiving Dex and 70% of those receiving the placebo).Chi-square tests were used to compare the percentages of patientswith emesis, anorexia, and fatigue in these two groups. Student’s t-test was used to compare changes in the symptom scores, as deter-mined using the questionnaires, between the two groups.

Results

Between April 2000 and March 2001, 70 patients wereenrolled in this study. Two patients assigned to the place-

Table 1 Patient characteristics

Number of patients

Dexamethasone Placebo

Enrolled patients 35 35Eligible patients 35 33

GenderMale 24 20Female 11 13

Age (years)Median 60 58Range 31–78 28–76

ECOG performance status0 11 101 23 212 1 2

Primary tumorColorectal cancer 34 30Gastric cancer 1 3

Chemotherapy regimenIrinotecan alone 24 22Irinotecan with Mitomycin C 11 11

ECOG: Eastern Cooperative Oncology Group

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bo group were excluded from the analysis because theyrefused to participate (in one case) and because of diseaseprogression before treatment in the other. No significantdifferences in patients’ characteristics between the twogroups were observed (Table 1). No patient had experi-enced moderate or severe emesis during previous chemo-therapy treatment, and none had emesis, anorexia, or fa-tigue prior to enrollment. All data on the effects of Dex onemesis, anorexia, and fatigue, and all safety data obtainedfrom the 68 patients in the analysis, were evaluable.

Activity

The percentages of patients experiencing complete pro-tection from acute emesis, delayed emesis, anorexia, andfatigue are evaluated (Table 2). High percentages ofcomplete prevention of acute emesis were achieved inboth groups using granisetron and Dex on day 1. Natu-rally, no significant difference in acute emesis was ob-served between the two groups. There was also no sig-nificant difference in complete protection from delayedemesis between patients receiving Dex (days 2–4) andthose receiving the placebo (days 2–4) (82.9% and78.8%). Furthermore, there were no statistically signifi-cant differences in complete protection from anorexia orfatigue between the two groups, although the percentageexperiencing complete protection from anorexia or fa-tigue tended to be larger among those receiving Dex thanthose using the placebo (62.9% and 77.1%, respectively,of patients receiving Dex, and 39.4% and 57.6%, respec-tively, of those receiving the placebo).

Regarding complete simultaneous protection from allthree symptoms, i.e., delayed emesis, anorexia, and fa-tigue, the Dex treatment group showed a marginally sig-nificant improvement compared to the placebo group(Dex, 60.0%; placebo, 36.4%; P=0.058) (Table 2).

Symptoms questionnaires were collected from 53 pa-tients (77.9%). Nine patients in the Dex group and six inthe placebo group did not submit the questionnaire (thequestionnaires were collected in the outpatient clinic,and these 15 patients had lost their questionnaires). Nodiscernible differences in patient characteristics (e.g.,gender, age, performance status) were observed between

the patients who answered the questionnaires and thosewho did not. Furthermore, no differences in patient char-acteristics were observed between patients who an-swered the questionnaires in the Dex and placebogroups. The change in score from the pretreatment ratingto the worst rating for each symptom were calculated,and the differences between the two groups were com-pared using Student’s t-test (Fig. 1). Although no signifi-cant differences in acute emesis or fatigue was observedbetween the two groups, significant improvements in de-layed emesis (P=0.004) and anorexia (P=0.028) wereobserved for the Dex patients.

Toxicity

Adverse effects other than emesis, anorexia, and fatigueseen in this study were examined (Table 3). Mild ormoderate adverse effects were reported in four (11.4%)patients receiving Dex and eight (24.2%) receiving theplacebo. None of these effects were thought to be relatedto either Dex or the placebo. The diarrhea observed infour patients was probably due to CPT-11, while the con-stipation observed in three patients was thought to be re-lated to the granisetron administered on day 1. Most ofthese adverse effects disappeared within a few days. Noinfectious toxicities were observed in either group.

Table 2 Comparison of percentages of patients experiencing complete protection from emesis, anorexia, and fatigue

Dexamethasone (n=35); placebo (n=33)

Complete protection Number Percent Number Percent P value

Acute emesis (day 1) 33 (94.3%) 31 (93.9%) NSDelayed emesis (day 2–6) 29 (82.9%) 26 (78.8%) NSAnorexia 22 (62.9%) 13 (39.4%) P=0.16Fatigue 27 (77.1%) 19 (57.6%) P=0.20Any delayed emesis, anorexia, or fatigue 21 (60.0%) 12 (36.4%) P=0.058

NS: not significant

Fig. 1 Mean (+SD) changes in self-recorded symptom scores be-tween the pretreatment rating and the worst rating experiencedduring the study period in the placebo group (right bars) and thedexamethasone (Dex) group (left bars). Asterisks indicate signifi-cant differences between the two groups, assessed using Student’st-test (*P<0.01, **P<0.05)

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Eleven sequential patients in the Dex group (seventreated with CPT alone and four treated with CPT andMMC) orally received 8 mg/day of Dex on days 2–4 inour outpatient clinic after their second course of chemo-therapy. The total number of Dex treatments in these pa-tients was 20. No severe late toxicities thought to be relat-ed to Dex were observed in any of the enrolled patients,including the above 11 patients. No treatment-relateddeaths occurred during the study or the follow-up period.

Discussion

Although acute emesis can be well controlled using sero-tonin antagonists and Dex [5, 17], the control of delayedemesis remains a problem for chemotherapy regimensthat contain emetogenic agents. Recently, some reportshave suggested that Dex may be an effective prophylac-tic for delayed emesis induced by CDDP and moderatelyemetogenic agents such as cyclophosphamide, doxorubi-cin, epirubicin, and carboplatin [18, 19]. CPT-11 is cate-gorized as an “intermediate risk” emetogenic agent ac-cording to the guidelines of the American Society ofClinical Oncology (which also states that some panelistsconsider CPT-11 to be a borderline high-risk agent).These guidelines recommend that patients be given Dex(4–8 mg) only as prophylaxis against acute emesis [5].Thus, the standard treatment for delayed emesis inducedby CPT-11 remains to be determined.

However, we have often observed patients treatedwith CPT-11 who experienced moderate-to-severe de-layed emesis that necessitated the discontinuation oftheir treatment, even when the antitumor effects werestill present. This study is the first report to assess the ef-ficacy of Dex for delayed emesis induced by CPT-11.

In addition, patients treated with CPT-11 sometimescomplain of unpleasant treatment-related symptoms,such as anorexia and fatigue. The incidences of grade 3/4anorexia and fatigue were reported to be 5% and13–15% in previous studies [4, 13]. According to thedrug information of irinotecan opened by OPSR, irinote-can-induced anorexia (grade 1–4) was observed in

74.1% of all the patients (1,134) who enrolled in clinicaltrials before the drug’s approval in Japan [21]. Mean-while, in another study of chemotherapy with CPT-11and mitomycin C, the incidence of fatigue (grade1–4)was reported to be 83% [20]. In severe cases, thesesymptoms can disrupt treatment, though only a few stud-ies on such “minor” symptoms associated with chemo-therapy have been performed [11, 15].

Dex is commonly used for cancer patients with an-orexia or fatigue, especially for end-of-life care [7], al-though evidence of its effectiveness is still being evaluat-ed. Thus, we also attempted to assess the efficacy of Dexfor preventing anorexia and fatigue induced by CPT-11.

In this study, we were unable to demonstrate the effec-tiveness of Dex in preventing delayed emesis. It is possiblybecause the sample size used in this study was too small todetect a statistically significant difference, or Dex was trulyineffective for delayed emesis induced by CPT-11. Howev-er, as to anorexia and fatigue, considering the percentage ofcomplete protection from anorexia and fatigue that tendedto be larger among those receiving Dex than those usingthe placebo (Dex, 62.9% and 77.1%; placebo, 39.4% and57.6%, respectively) and the percentage of patients whoexperienced complete simultaneous protection from de-layed emesis, anorexia, and fatigue (Dex, 60.0%; placebo,36.4%), we believe that Dex may have some beneficial ef-fect to reduce such post-chemotherapy symptoms.

The low compliance of sequential assessment ofsymptom scale was one of the limitations of our study,which may be because this assessment was not informedenough to patients and 15 patients had lost their ques-tionnaires. We consider we were unable to reach a defi-nite conclusion from the assessment of symptom scale.

Infection is a concern in patients who are continuouslytreated with Dex. In this study, no significant difference ininfectious toxicities was observed between the twogroups. Although we intended to observe the patients onlyduring their hospitalization, all patients treated with Dexon days 2–4 after their second course of chemotherapywere followed using their medical records; no additionaladverse effects were observed in any of these patients. Incomparison to other studies using 20–24 mg of Dex perweek in conjunction with chemotherapy [3, 14], our 16-mg-per-week dosage of Dex (32 mg over 2 weeks)seemed to be relatively safe. Although physicians and pa-tients must aware of the risk of other toxicities related toDex, such as hyperglycemia, hypertension, and osteoporo-sis, the administration of Dex on days 1–4 of chemothera-py regimens containing CPT-11 is probably safe.

In conclusion, treatment with Dex on days 2–4 ofchemotherapy regimens containing CPT-11 may be ef-fective for reducing post-chemotherapy symptoms, spe-cifically anorexia and fatigue. Furthermore, the toxicitiesare acceptable with this protocol. Further studies aimedat establishing the optimal dose and duration of Dex ad-ministration are warranted.

Table 3 Toxicity profiles

Dexamethasone Placebo

Adverse effects Grade 1/2/3/4 Grade 1/2/3/4

Fever 2/0/0/0 3/0/0/0Diarrhea 1/0/1/0 2/0/0/0Constipation 0/0/0/0 0/3/0/0Abdominal pain 0/0/0/0 3/0/0/0Hiccup 2/0/0/0 0/0/0/0Hypertension 1/0/0/0 0/0/0/0Liver dysfunction 1/0/0/0 0/0/0/0Insomnia 0/0/0/0 1/0/0/0

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