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Contents lists available at ScienceDirect

Lung Cancer

jou rn al hom epage: www.elsev ier .com/ locate / lungcan

prepitant in patients with advanced non-small-cell lung cancereceiving carboplatin-based chemotherapy�

asuhiro Itoa, Masato Karayamaa,b, Naoki Inuia,c,∗, Shigeki Kuroishid, Hideki Nakanoe,utaro Nakamuraa, Koshi Yokomuraf, Mikio Toyoshimag, Toshihiro Shiraih,asafumi Masudai, Takashi Yamadaj, Kazumasa Yasudak, Hiroshi Hayakawal,

akafumi Sudaa, Kingo Chidaa

Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, JapanDepartment of Clinical Oncology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, JapanDepartment of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, JapanDepartment of Respiratory Medicine, Ensyu Hospital, 1-1-1 Chuou, Hamamatsu 430-0929, JapanDepartment of Respiratory Medicine, Japanese Red Cross Hamamatsu Hospital, 1088-1 Kobayashi, Hamamatsu 434-8533, JapanDepartment of Respiratory Medicine, Seirei Mikatahara General Hospital, 3453 Mikatahara-cho, Hamamatsu 433-8558, JapanDepartment of Respiratory Medicine, Hamamatsu Rosai Hospital, 25 Shougen-cho, Hamamatsu 434-8525, JapanDepartment of Respiratory Medicine, Shizuoka General Hospital, 4-27-1 Kita-ando, Shizuoka 420-0881, JapanDepartment of Respiratory Medicine, Shizuoka City Shimizu Hospital, 1231 Miyakami, Shizuoka 424-8636, JapanDepartment of Respiratory Medicine, Shizuoka City Shizuoka Hospital, 10-93 Ote-cho, Shizuoka 420-8630, JapanDepartment of Respiratory Medicine, Iwata City Hospital, 513-2 Ohkubo, Iwata 438-8550, JapanDepartment of Respiratory Medicine, Tenryu Hospital, 4201-2 Oro, Hamamatsu 434-8511, Japan

r t i c l e i n f o

rticle history:eceived 29 November 2013eceived in revised form 13 March 2014ccepted 17 March 2014

eywords:ntiemeticprepitantarboplatinhemotherapy-induced nausea andomitingon-small-cell lung canceremetrexed

a b s t r a c t

Objectives: Chemotherapy-induced nausea and vomiting (CINV) is an unanswered problem in can-cer therapy. We evaluated the efficacy and safety of triple antiemetic therapy with aprepitant, a5-hydroxytryptamine-3 (5-HT3) receptor antagonist, and dexamethasone in patients with advancednon-small-cell lung cancer (NSCLC) who received carboplatin-based first-line chemotherapy.Methods: Chemotherapy-naïve patients with NSCLC were enrolled in this randomized phase-II study.Patients were randomized to standard antiemetic therapy with a 5-HT3 receptor antagonist and dexa-methasone, and aprepitant add-on triple antiemetic therapy. The primary endpoint was the completeresponse rate (no vomiting and no rescue therapy) during the 120 h post-chemotherapy.Results: A total of 134 patients were assigned randomly to the aprepitant group or the control group. Theaprepitant group and the control group showed an overall complete response rate of 80.3% (95% confi-dence interval (CI), 69.2–88.1%) and 67.2% (95% CI, 55.3–77.2%; odds ratio (OR), 0.50; 95% CI, 0.22–1.10;p = 0.085), respectively. Among patients taking carboplatin and pemetrexed, adding aprepitant signifi-cantly improved the complete response rate in the overall phase (83.8% in the aprepitant group and 56.8%

in the control group; OR, 0.26; 95% CI, 0.08–0.70; p < 0.01) and the delayed phase (86.5% in the aprepitantgroup and 59.1% in the control group; OR, 0.23; 95% CI, 0.07–0.65; p < 0.01).Conclusion: Carboplatin-based chemotherapy has considerable emetic potential. Triple antiemetic ther-apy with aprepitant, a 5-HT3 receptor antagonist, and dexamethasone improved the control of CINVprevention in patients receiving carboplatin and pemetrexed chemotherapy.

© 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Ito Y, et al. Aprepitant in patients withchemotherapy. Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungca

� This trial is registered number UMIN000010018.∗ Corresponding author at: Hamamatsu University School of Medicine, 1-20-1andayama, Hamamatsu 431-3192, Japan Tel.: +81 53 435 2263;

ax: +81 53 435 2386.E-mail address: inui@hama-med.ac.jp (N. Inui).

ttp://dx.doi.org/10.1016/j.lungcan.2014.03.017169-5002/© 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Lung cancer is a leading cause of cancer-related death in many

advanced non-small-cell lung cancer receiving carboplatin-basedn.2014.03.017

countries [1,2]. Platinum combinations have improved survivaland quality of life (QOL) in patients with advanced non-small-celllung cancer (NSCLC) [2,3]. In the management of NSCLC, cisplatinand carboplatin are used as platinum compounds. Compared with

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isplatin, carboplatin has less neural, emetic, and renal toxicity,nd can be administered conveniently without prolonged hydra-ion. These advantages and almost equivalent efficacy to cisplatin

ake carboplatin an optimal chemotherapy agent [2,3]. Carbo-latin in combination with third-generation antitumor agents isidely used as first-line chemotherapy in advanced NSCLC [2,3].

Chemotherapy-induced nausea and vomiting (CINV) is one ofhe most feared and distressing adverse events in cancer treatments4–8]. Without adequate management, nausea and vomiting occursn ≤80% of patients receiving cancer therapy [4,7]. CINV can impairOL, deteriorate nutritional states, and even have negative impactsn the continuation of chemotherapy [5,9,10]. Furthermore, inade-uate control of emesis may lead to anticipatory emesis on the nextccasion of chemotherapy, which cannot be controlled easily byntiemetic agents [6,11]. Less toxic chemotherapy is important toetain good performance status and enable further chemotherapyn multimodal treatment for NSCLC, so prevention of CINV remainshe most important issue in supportive therapy.

According to the frequency and power of emetic action,hemotherapy agents are categorized as “highly emetogenichemotherapy” (HEC), “moderately emetogenic chemotherapy”MEC) as well as “low”, and “minimal” emetogenic agents [6,12,13].or MEC regimens, antiemetic therapy with dexamethasone and

5-hydroxytryptamine-3 (5-HT3) receptor antagonist is rec-mmended, and a neurokinin-1 (NK1) receptor antagonist isonsidered a therapeutic option in selected cases [5,6,12,13]. How-ver, the control of nausea and vomiting (especially in the delayedhase) in patients undergoing MEC is not acceptable even ifrophylactic treatment with a 5-HT3 receptor antagonist and dexa-ethasone is administered [9,14–16].Aprepitant is a selective NK1 receptor antagonist [5]. Several

tudies have demonstrated that adding aprepitant to doublet ther-py with a 5-HT3 receptor antagonist and dexamethasone canontrol CINV in HEC regimens [17–19]. Few studies have demon-trated the efficacy of aprepitant in MEC regimens [15]. Rapoportt al. reported that adding aprepitant reduced CINV events inatients undergoing a broad range of MEC regimens and tumorypes, but they mainly targeted anthracycline and cyclophos-hamide therapy in patients with breast cancer [16], which is nowegarded as a HEC regimen [12,13].

Carboplatin is categorized as a MEC agent that induces eme-is in the delayed phase [5,6,12,13]. Despite being used widelyn combination, few data are available on the emetic potential ofarboplatin-containing therapy [6] and the benefit of additionalprepitant in this regimen.

In the present study, we conducted a randomized phase-II studyo compare the efficacy and safety of triple antiemetic therapyith aprepitant, a 5-HT3 receptor antagonist and dexamethasone

ersus active control therapy with a 5-HT3 receptor antagonist andexamethasone in patients with advanced NSCLC who receivedarboplatin-based first-line chemotherapy. We assessed the com-lete response rate (no vomiting and no rescue therapy) to evaluatehe utility of adding aprepitant as a prophylactic antiemetic forarboplatin-containing chemotherapy.

. Patients and methods

.1. Study design

This study was a multicenter, randomized, open-label, parallel-

Please cite this article in press as: Ito Y, et al. Aprepitant in patients withchemotherapy. Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungc

roup, phase-II trial conducted in accordance with the Declarationf Helsinki. The study protocol was approved by the Reviewoard of each participating institution. Each patient gave written

nformed consent to be included in the study.

PRESSxxx (2014) xxx–xxx

2.2. Patient eligibility

Chemotherapy-naïve patients with pathologically confirmedinoperable stage-IIIB or -IV NSCLC aged ≥20 years and who receivedcarboplatin-based chemotherapy were eligible for inclusion. Addi-tional eligibility criteria also comprised adequate hematopoietic,renal and hepatic function. Exclusion criteria included nausea andvomiting within 24 h or use of antiemetic agents within 48 h beforeadministration of chemotherapy, use of pimozide, and uncontrolleddiabetes mellitus. Patients were excluded if they had symptomaticbrain metastasis, gastrointestinal obstruction, or an active gas-trointestinal ulcer because they were likely to induce nausea andvomiting regardless of chemotherapy.

2.3. Treatment schedule

Patients with squamous cell carcinoma were treated with pacli-taxel and carboplatin (paclitaxel 200 mg/m2 and carboplatin atan area under the curve (AUC) of 6 on day 1 of a 21-day cycle).Patients with non-squamous NSCLC were treated with pemetrexedand carboplatin (pemetrexed 500 mg/m2 and carboplatin at an AUCof 6 on day 1 of a 21-day cycle) or paclitaxel and carboplatin. Insome eligible cases, bevacizumab was added. The carboplatin dosewas calculated according to the Calvert formula. The glomerularfiltration rate was estimated from the Cockcroft–Gault formula.Patients were assigned randomly to receive standard antiemetictherapy (control group) or aprepitant combination therapy (aprepi-tant group). Randomization was done centrally using a computerprogram and stratified by sex and non-platinum agent. The controlgroup received standard antiemetic doublet therapy with a first-generation 5-HT3 antagonist on day 1 and dexamethasone (8 mg)on days 1–3. For the aprepitant group, aprepitant (125 mg) on day 1and 80 mg on days 2–3 was given in addition to standard antiemeticdoublet therapy. When patients took paclitaxel or pemetrexed,they received prophylactic dexamethasone, H1 and H2 blockers,folic acid, and vitamin B12 according to the package insert in Japan.In the case of paclitaxel, the dose of 12 mg dexamethasone wasadded at day 1 to prevent anaphylactic reactions. The dose of dexa-methasone was reduced in the aprepitant group according to thosein previous studies [15–17,19]. Additional antiemetic agents andother supportive treatments were administered at the discretionof the treating physicians.

2.4. Evaluation of response and toxicity

Patients completed a daily questionnaire regarding the fre-quency of vomiting and scoring of nausea during 5 days. Physiciansrecorded the use of additional antiemetic therapies during thestudy period. Complete response was defined as the proportion ofpatients with no vomiting episode and no rescue therapy. Adverseevents were graded using the Common Toxicity Criteria (version3.0).

2.5. Statistical analyses

The primary endpoint was the complete response rate in theoverall phase (during the 120 h after administration of chemother-apy agents). Secondary endpoints were the complete responserate in the acute (during the first 24 h after administration ofchemotherapy agents) and delayed phase (from 24 h to 120 h afterchemotherapy); nausea in the overall phase, acute and delayedphase; and safety. At randomization, 134 patients were required to

advanced non-small-cell lung cancer receiving carboplatin-basedan.2014.03.017

achieve 80% statistical power with a two-sided ̨ error of 0.05 basedon the binomial test assuming an expected complete response rateduring the first cycle in the aprepitant group of 87% and in thecontrol group of 67% [17,18,20]. Efficacy analyses were based on

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Fig. 2. Complete response rate in acute, delayed, and overall phases. Bar graphsshow the percentage of patients achieving a complete response defined in acute(0–24 h), delayed (24–120 h), and overall phases (0–120 h). The complete response

Fig. 1. Study profile.

atients who received chemotherapy, took the study drugs, andad at least one post-treatment assessment. Frequency of vomi-ing and nausea were compared using the Wilcoxon rank-sum test,nd other categorized groups were compared using the chi-squaredest. The comparison within each group was conducted using the

cNemar test. All values were analyzed using JMP vers5.0.1 (SASnstitute Japan; Tokyo, Japan). All statistical tests were two-sided,nd p < 0.05 was considered significant.

. Results

.1. Patient characteristics

One hundred thirty-four patients were enrolled and assignedandomly to the aprepitant group or the control group (Fig. 1).atient characteristics are listed in Table 1. The median age at

Please cite this article in press as: Ito Y, et al. Aprepitant in patients withchemotherapy. Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungca

andomization was 67 years (range, 39–84 years). Twenty-fouratients (17.9%) were female. Ninety-seven (72.4%) patients hadtage-IV disease, and 18 (13.4%) had stable brain metastases that

able 1atient characteristics.

Aprepitant(n = 67)

Control(n = 67)

Age, years 67 (34–84) 66 (44–81)Sex

Male 56 (83.6) 54 (80.6)Female 11 (16.4) 13 (19.4)

Performance statusa

0 47 (70.1) 47 (70.1)1 18 (26.9) 20 (29.9)2 2 (3.0) 0 (0)

StageIIIB 12 (17.9) 13 (19.4)IV 50 (74.6) 47 (70.2)Recurrence 5 (7.5) 7 (10.4)

HistologyAdenocarcinoma 50 (74.6) 50 (74.6)Squamous cell carcinoma 12 (17.9) 10 (14.9)Other 5 (7.5) 7 (10.4)

Chemotherapy regimenCarboplatin + paclitaxel 27 (40.3) 21 (31.3)Carboplatin + paclitaxel + bevacizumab 3 (4.5) 2 (3.0)Carboplatin + pemetrexed 30 (44.8) 36 (53.7)Carboplatin + pemetrexed + bevacizumab 7 (10.4) 8 (11.9)

Frequency of alcohol drinking/week0 35 (52.2) 31 (46.3)1–6 21 (31.3) 18 (26.9)>7 11 (16.4) 16 (23.9)Unknown 0 (0) 2 (3.0)

Brain metastasis 11 (16.4) 7 (10.4)History of motion sickness 5 (7.5) 1 (1.5)History of vomiting during pregnancy 1 (1.5) 1 (1.5)Use of opioids 9 (13.4) 5 (7.5)

ata are numbers (percentage) or median (range).a Performance status was determined according to the Eastern Cooperative Oncol-

gy Group Scale.

rate was defined as the proportion of patients with no vomiting episode and norescue therapy. The black bar denotes the aprepitant group, the gray bar the controlgroup.

were asymptomatic. Baseline demographics were well balancedbetween the two groups (Table 1). Although more patients in theaprepitant group received carboplatin and paclitaxel combinationchemotherapy and more patients in the control group receivedcarboplatin and pemetrexed combination chemotherapy, the dif-ference was not significant (p = 0.216).

3.2. Efficacy

The aprepitant group showed a better overall complete responserate of 80.3% (95% confidence interval (CI), 69.2–88.1%) comparedwith that of 67.2% (95% CI, 55.3–77.2%) for the control group, butthe difference was not significant (odds ratio (OR), 0.50; 95% CI,0.22–1.10; p = 0.085; Fig. 2). The aprepitant group demonstrated atrend toward a better complete response rate in the delayed phase(OR, 0.49; 95% CI, 0.21–1.08; p = 0.079) but complete response in theacute phase was equivalent between the two groups (OR, 1.02; 95%CI, 0.04–26.02; p = 0.99). The complete response rate with respect tochemotherapy agents is shown in Table 2. Among patients under-going carboplatin and pemetrexed (with or without bevacizumab),adding aprepitant significantly improved the complete responserate in the overall phase (83.8% in the aprepitant group and 56.8%in the control group; OR, 0.26; 95% CI, 0.08–0.70; p < 0.01) and thedelayed phase (86.5% in aprepitant group and 59.1% in the con-trol group, OR 0.23, 95% CI; 0.07–0.65, p < 0.01). Conversely, amongpatients who received carboplatin and paclitaxel (with or withoutbevacizumab), no significant difference was observed in the acute,delayed, or overall complete response rate between the two groups.

The occurrence of nausea was evaluated using patient ques-tionnaires. There was no significant difference in the frequencyof nausea between the aprepitant group and the control group(acute phase: 25.0% versus 20.0%, p = 0.51; delayed phase: 46.7%versus 56.7%, p = 0.27; overall phase: 46.7% versus 58.3%; p = 0.20,respectively). In patients receiving carboplatin and pemetrexed, theaprepitant group showed a slightly reduced occurrence of nausea

advanced non-small-cell lung cancer receiving carboplatin-basedn.2014.03.017

in delayed and overall phases, but it was not significant (delayedphase: 45.2% versus 60.5%, p = 0.20; overall phase: 45.2% versus60.5%; p = 0.20, respectively). Rescue antiemetic treatments wereadministered in 15.2% of the aprepitant group and in 28.4% of the

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Table 2Complete response rate according to chemotherapy regimens: (A) carboplatin + pemetrexed ± bevacizumab and (B) carboplatin + paclitaxel ± bevacizumab.

(A) Carboplatin + pemetrexed ± bevacizumab

Phase Aprepitant (n = 37) Control (n = 44) Odds ratio (95%CI) p-Value

Acute phase 97.3 (86.1–99.5) 97.7 (88.2–99.6) 1.19 (0.05–30.90) 0.90Delayed phase 86.5 (72.0–94.1) 59.1 (44.4–72.3) 0.23 (0.07–0.65) <0.01Overall phase 83.8 (68.9–92.3) 56.8 (42.2–57.8) 0.26 (0.08–0.70) <0.01

(B) carboplatin + paclitaxel ± bevacizumab

Phase Aprepitant (n = 29) Control (n = 23) Odds ratio (95%CI) p-Value

Acute phase 100.0 (NE) 100.0 (NE) NE NEDelayed phase 75.9 (57.9–87.8) 87.0 (67.9–95.5) 2.12 (0.51–10.89) 0.31Overall phase 75.9 (57.9–87.8) 87.0 (67.9–95.5) 2.12 (0.51–10.89) 0.31

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omplete response rate is defined as no vomiting and no rescue therapy.ata are the percentage (95% confidence interval).I, confidence interval; NE, not estimable.

ontrol group (p = 0.07). In patients taking carboplatin and peme-rexed, adding aprepitant reduced the need for rescue antiemeticreatment (16.2% versus 36.4%, p = 0.04). Conversely, aprepitant didot influence the use of rescue treatment in paclitaxel regimens13.8% versus 13.0%, p = 0.94).

.3. Safety

All 134 patients (including one patient who could not completehemotherapy because of anaphylactic shock due to paclitaxel)ere included in the safety analysis. The prevalence of major

dverse events is shown in Table 3. The most common severe tox-city that reached grade 3 or 4 in both groups was leukopenia,eutropenia, and thrombocytopenia. One patient in the aprepitantroup had a hypersensitivity reaction to paclitaxel (grade 3). Moreatients in the control group developed nausea and vomiting than

n the aprepitant group (65.7% versus 47.8%, p < 0.05; 23.9% versus.5%, p < 0.05; respectively), whereas the prevalence of hiccups wasreater (but not significantly) in the aprepitant group (p = 0.12). Alldverse events were tolerated. There was no irreversible toxicityr death considered to be related to treatment.

. Discussion

Please cite this article in press as: Ito Y, et al. Aprepitant in patients withchemotherapy. Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungc

Antiemetic management has improved during the last twoecades, but CINV remains an unanswered problem in cancer ther-py. Here, we assessed the efficacy and safety of triple antiemeticherapy with aprepitant, a 5-HT3 receptor antagonist and

able 3dverse events.

Aprepitant (n = 67)

Grades 1–4 Grad

Hematologic toxicityLeukopenia 26 (38.8) 9 (1Neutropenia 26 (38.8) 10 (Anemia 27 (40.3) 2 (3Thrombocytopenia 20 (29.9) 4 (6

Non-hematologic toxicityHepatotoxicity 15 (22.4) 0

Nephrotoxicity 2 (3.0) 0

Nausea 32 (47.8)* 1 (1Vomiting 5 (7.5)* 0

Constipation 17 (25.4) 0

Diarrhea 2 (3.0) 0

Fatigue 27 (40.3) 1 (1Allergic reaction 2 (3.0) 1 (1Hiccup 12 (17.9) 0

alues are numbers (percentage).* p < 0.05 compared with the control group.

dexamethasone in NSCLC patients who received carboplatin-basedfirst-line chemotherapy. Triple antiemetic therapy was associatedwith non-significant improvement of the complete response rateand reduction in CINV events in overall and delayed phases. Inpatients taking carboplatin and pemetrexed, aprepitant signifi-cantly improved the complete response rate and reduced emesisand nausea. On the other hand, additional aprepitant provided nobenefit in carboplatin and paclitaxel regimen. A complete responserate without aprepitant of approximately 60% suggested that car-boplatin and pemetrexed combination therapy was an unpleasantrisk of CINV. Aprepitant-containing antiemetic therapy may be avaluable option in patients receiving carboplatin and pemetrexedchemotherapy.

The emetogenic risk classification is defined based on the acutepotency of a single agent. The emetogenic level of combinationtherapy is determined according to the agent with the great-est degree of emetic risk [12] and is not based on the observedevidence of combination therapy [6,9]. Despite the widespreaduse of carboplatin in cancer therapy, only a few studies haveevaluated the risk of emesis of carboplatin-based therapy. In asingle-arm observational study, it was reported that 14% and33% of patients receiving a carboplatin-containing regimen withstandard antiemetic prophylaxis using a 5-HT3 receptor antago-nist and dexamethasone experienced moderate-to-severe nausea

advanced non-small-cell lung cancer receiving carboplatin-basedan.2014.03.017

and vomiting in acute and delayed phases, respectively [20]. In thepresent study, the overall complete response rate in patients whodid not take aprepitant was 65.1%, and it was due mostly to events inthe delayed phase. These data suggest that carboplatin-containing

Control (n = 67)

es 3–4 Grades 1–4 Grades 3–4

3.4) 35 (52.2) 14 (20.9)14.9)* 35 (52.2) 14 (20.9).0) 20 (29.9) 2 (3.0).0) 18 (26.9) 9 (13.4)

18 (26.9) 1 (1.5)3 (4.5) 0

.5) 44 (65.7) 1 (1.5)16 (23.9) 019 (28.4) 0

5 (7.5) 0.5) 37 (55.2) 3 (4.5).5) 2 (3.0) 0

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ARTICLEUNG-4573; No. of Pages 6

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ombination chemotherapy has considerable emetic potential.ntiemetic therapy should aim to minimize or eliminate nauseand vomiting in all patients receiving chemotherapy [16]. Ratherhan withholding more effective antiemetics for subsequent uset the time of antiemetic failure, maximally effective antiemeticss first-line therapy are recommended [6]. In the present study,prepitant added to standard antiemetic prophylaxis improvedverall and delayed complete response rates in carboplatin andemetrexed chemotherapy, which suggested improvement ofntiemetic control. That is, the addition of aprepitant is a feasibleption.

CINV has two distinct phases that have different mechanisms5]. Therefore, there are different ways of approaching CINV. Incute-phase CINV, 5-HT3 is thought to be the main causativegent, which can be controlled by a 5-HT3 receptor antagonist andexamethasone [21,22]. In the present study, antiemetic agentsith a 5-HT3 receptor antagonist and dexamethasone controlled

cute-phase CINV, which suggested that doublet therapy with a 5-T3 receptor antagonist and dexamethasone is suitably efficient

o prevent acute-phase CINV in carboplatin-based therapy. Con-ersely, substance P and the NK1 receptor system have a greaternput in delayed-phase CINV than the 5-HT3 system [5]. Doubletherapy without aprepitant has not demonstrated satisfactory out-omes for delayed-phase CINV in HEC or in anthracycline andyclophosphamide therapy [15–19]. In the present study, >30% ofatients could not control delayed-phase CINV without aprepitant.riple therapy with aprepitant improved the complete responseate in the delayed phase with a tendency toward significancep = 0.079; OR, 0.49; 95% CI, 0.21–1.08). The magnitude of the bene-t in antiemesis with aprepitant in delayed-phase CINV was 13.1%,hich was greater than the difference of 10% generally considered

o be clinically relevant [23]. Clinicians are likely to underestimateelayed-phase CINV [14], although it develops more frequentlyhan acute-phase CINV [9,15–17,19,21,22]. Patients who have notxperienced acute-phase CINV often suffer from delayed-phaseINV [9,14]. Additionally, delayed-phase CINV has stronger nega-ive effects on QOL compared with acute-phase CINV [9]. Improvingelayed-phase CINV by aprepitant could benefit patients receivinghemotherapy.

There was a significant difference in the complete responseate according to the non-platinum agent that was combinedith carboplatin. The complete response rate was 56.8% in the

8 patients who received carboplatin and pemetrexed withoutprepitant, which was comparable with that of 50–60% in patientsho received HEC regimens without aprepitant in previous studies

17–19,21,22]. Triple antiemetic therapy with aprepitant, a 5-HT3eceptor antagonist, and dexamethasone significantly improvedhe complete response rate (p < 0.01, Table 2) in patients takingarboplatin and pemetrexed. This result suggested a relativelyigh emetogenic potential of carboplatin-pemetrexed combinationherapy, and that additional aprepitant therapy can prevent nauseand vomiting in those taking a carboplatin and pemetrexed regi-en. In contrast, patients who received carboplatin and paclitaxel

chieved a high complete response rate of 87% even without aprepi-ant, and additional aprepitant provided no benefit in this regimen.hese differences might result from administration of a high-doseorticosteroid to prevent anaphylactic reactions due to paclitaxel.hemotherapy agents categorized as MEC contain a wide spectrumf emetic potential (30–90%) [6,12,13], and limited data are avail-ble on the emetic potential of combination therapy [6]. Althoughhe emetogenic risk of paclitaxel is categorized as identical to thatf pemetrexed, combination therapy with carboplatin and peme-

Please cite this article in press as: Ito Y, et al. Aprepitant in patients withchemotherapy. Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungca

rexed might synergistically have higher emetogenic potency thanarboplatin and paclitaxel.

The prevalence of clinical and laboratory adverse events wasimilar between groups except for hiccups in the aprepitant group

PRESSxx (2014) xxx–xxx 5

and neutropenia in the control group. Vomiting and nausea werecommon events in the control group. Adding aprepitant did notenhance the toxicity of chemotherapy. Although we need to con-sider the cost, these safety profiles enable us to use aprepitantwithout hesitation to improve emetic control and cancer manage-ment.

When considering the risk of CINV and the application ofantiemetics, evaluating patient-related factors such as age, sex, his-tory of chemotherapy, motion sickness, emesis in pregnancy, oralcohol consumption are important. Recently, Tanioka et al. evalu-ated the efficacy of antiemetics in non-alcohol-consuming femalesaged <70 years receiving MEC regimens (mainly carboplatin andpaclitaxel) [24]. The complete response rate in the overall phasewas 52% even with high-dose dexamethasone (20 mg at day 1 and8 mg at days 2 and 3) and a 5-HT3 receptor antagonist, whichwas different from that of 81% in patients undergoing carboplatinand paclitaxel in the present study. The difference in the completeresponse rate may have resulted from patient-related risk factorsfor CINV because patients in the current study were predominantlymale and elderly, and half of the patients consumed alcohol. Onmultivariate logistic regression analysis, age <65 years (OR, 4.18;95% CI, 1.81–10.11; p = 0.002) was associated with worse outcomein overall complete response. Being male, alcohol consumption, andthe addition of aprepitant were not significantly predictive of CINV.Consensus guidelines place greater emphasis on the emetogenicpotential and dose of the chemotherapy drug, but greater consider-ation might need to be given to patient-related risk in future studies[25].

The present study had limitations. First, first-generation 5-HT3receptor antagonists were used for antiemetic treatment. In HEC,combination of a second-generation 5-HT3 receptor antagonist,palonosetron (which has a greater binding affinity and a prolongedhalf-life), and dexamethasone is superior to a first-generation 5-HT3 receptor antagonist and dexamethasone [21]. Some guidelinesrecommend palonosetron as the preferred 5-HT3 receptor antago-nist in patients with MEC [6,12]. However, whether palonosetron incombination with dexamethasone is superior to other 5-HT3 recep-tor antagonists in MEC regimens is not known [21,24]. The possiblesuperiority of palonosetron with aprepitant is also not known. Theadditive effect caused by adding aprepitant in the present studymay be attenuated in triple therapy with palonosetron. Second,dexamethasone was used for the antiemesis and prophylaxis ofanticancer agent-induced anaphylaxis. The dose of dexamethasonewas set according to the package insert in Japan, and was differentbetween patients receiving paclitaxel and pemetrexed. Althoughcorticosteroids in antiemetic therapy sometimes induce adverseeffects [26], an increased prevalence of infection and poor glycemiccontrol was not observed. Third, this is randomized phase-II studywith limited sample size. The number of cases might not be enoughto evaluate the risk of CINV and the application of antiemetics usingmultivariate logistic regression analysis. Trials with a larger pop-ulation and selected patients can help to choose the patients whoneed aprepitant-containing antiemetic therapy. In particular, stud-ies focusing on a carboplatin and pemetrexed regimen are neededto confirm our results.

5. Conclusion

Carboplatin-based chemotherapy had relatively high emeticpotential, especially in carboplatin and pemetrexed combinationchemotherapy. Triple antiemetic therapy with aprepitant, a 5-HT3receptor antagonist, and dexamethasone may be an effective and

advanced non-small-cell lung cancer receiving carboplatin-basedn.2014.03.017

feasible prophylactic treatment in patients receiving carboplatinand pemetrexed. Further studies are warranted to determine thespecific patient characteristics and regimens that could gain benefitfrom such treatment.

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onflict of interest statement

All authors declare no actual or potential conflicts of interest.

cknowledgment

No financial support was provided for this study.

eferences

[1] Reck M, Heigener DF, Mok T, Soria JC, Rabe KF. Management of non-small-celllung cancer: recent developments. Lancet 2013;382:709–19.

[2] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics.CA Cancer J Clin 2011;61:69–90.

[3] Azzoli CG, Baker Jr S, Temin S, Pao W, Aliff T, Brahmer J, et al. American Societyof Clinical Oncology Clinical Practice Guideline update on chemotherapy forstage IV non-small-cell lung cancer. J Clin Oncol 2009;27:6251–66.

[4] Roscoe JA, Morrow GR, Hickok JT, Stern RM. Nausea and vomiting remain asignificant clinical problem: trends over time in controlling chemotherapy-induced nausea and vomiting in 1413 patients treated in community clinicalpractices. J Pain Symptom Manage 2000;20:113–21.

[5] Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med2008;358:2482–94.

[6] Roila F, Herrstedt J, Aapro M, Gralla RJ, Einhorn LH, Ballatori E, et al. Guide-line update for MASCC and ESMO in the prevention of chemotherapy- andradiotherapy-induced nausea and vomiting: results of the Perugia consensusconference. Ann Oncol 2010;21 Suppl 5:v232–43.

[7] Griffin AM, Butow PN, Coates AS, Childs AM, Ellis PM, Dunn SM, et al. On thereceiving end. V: Patient perceptions of the side effects of cancer chemotherapyin 1993. Ann Oncol 1996;7:189–95.

[8] Molassiotis A, Stricker CT, Eaby B, Velders L, Coventry PA. Understanding theconcept of chemotherapy-related nausea: the patient experience. Eur J CancerCare (Engl) 2008;17:444–53.

[9] Bloechl-Daum B, Deuson RR, Mavros P, Hansen M, Herrstedt J. Delayed nauseaand vomiting continue to reduce patients’ quality of life after highly and mod-erately emetogenic chemotherapy despite antiemetic treatment. J Clin Oncol2006;24:4472–8.

10] Osoba D, Zee B, Warr D, Kaizer L, Latreille J, Pater J. Quality of lifestudies in chemotherapy-induced emesis. Oncology 1996;53(Suppl 1):92–5.

11] Roscoe JA, Morrow GR, Aapro MS, Molassiotis A, Olver I. Anticipatory nauseaand vomiting. Support Care Cancer 2011;19:1533–8.

Please cite this article in press as: Ito Y, et al. Aprepitant in patients withchemotherapy. Lung Cancer (2014), http://dx.doi.org/10.1016/j.lungc

12] Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC, Somerfield MR, et al.Antiemetics American Society of Clinical Oncology clinical practice guidelineupdate. J Clin Oncol 2011;29:4189–98.

13] Ettinger DS, Armstrong DK, Barbour S, Berger MJ, Bierman PJ, Bradbury B, et al.J Natl Compr Canc Netw 2012;10:456–85.

[

[

PRESSxxx (2014) xxx–xxx

14] Grunberg SM, Deuson RR, Mavros P, Geling O, Hansen M, Cruciani G, et al. Inci-dence of chemotherapy-induced nausea and emesis after modern antiemetics.Cancer 2004;100:2261–8.

15] Warr DG, Hesketh PJ, Gralla RJ, Muss HB, Herrstedt J, Eisenberg PD, et al. Efficacyand tolerability of aprepitant for the prevention of chemotherapy-induced nau-sea and vomiting in patients with breast cancer after moderately emetogenicchemotherapy. J Clin Oncol 2005;23:2822–30.

16] Rapoport BL, Jordan K, Boice JA, Taylor A, Brown C, Hardwick JS, et al.Aprepitant for the prevention of chemotherapy-induced nausea and vomi-ting associated with a broad range of moderately emetogenic chemotherapiesand tumor types: a randomized, double-blind study. Support Care Cancer2010;18:423–31.

17] Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, Julie MaG, Eldridge K, Hipple A,et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standardantiemetic therapy improves control of chemotherapy-induced nausea andvomiting. Results from a randomized, double-blind, placebo-controlled trialin Latin America. Cancer 2003;97:3090–8.

18] Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, de Wit R, et al. Theoral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind,placebo-controlled trial in patients receiving high-dose cisplatin – the Aprepi-tant Protocol 052 Study Group. J Clin Oncol 2003;21:4112–9.

19] Schmoll HJ, Aapro MS, Poli-Bigelli S, Kim HK, Park K, Jordan K, et al. Comparisonof an aprepitant regimen with a multiple-day ondansetron regimen, both withdexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. AnnOncol 2006;17:1000–6.

20] Waqar MA, Chitneni P, Williams K, Goodgame BW, Gao F, Govindan R, et al.A prospective study on the incidence of delayed nausea and vomiting follow-ing administration of carboplatin containing regimens for treatment of cancerwithout prophylactic aprepitant. J Clin Oncol 2008;26 S:20626.

21] Saito M, Aogi K, Sekine I, Yoshizawa H, Yanagita Y, Sakai H, et al. Palonosetronplus dexamethasone versus granisetron plus dexamethasone for prevention ofnausea and vomiting during chemotherapy: a double-blind, double-dummy,randomised, comparative phase III trial. Lancet Oncol 2009;10:115–24.

22] Celio L, Frustaci S, Denaro A, Buonadonna A, Ardizzoia A, Piazza E, et al.Palonosetron in combination with 1-day versus 3-day dexamethasonefor prevention of nausea and vomiting following moderately emetogenicchemotherapy: a randomized, multicenter, phase III trial. Support Care Cancer2011;19:1217–25.

23] Olver IN. Antiemetic study methodology: recommendations for future studies.Oncology 1996;53(Suppl 1):96–101.

24] Tanioka M, Kitao A, Matsumoto K, Shibata N, Yamaguchi S, Fujiwara K, et al.A randomised, placebo-controlled, double-blind study of aprepitant in non-drinking women younger than 70 years receiving moderately emetogenicchemotherapy. Br J Cancer 2013;109:859–65.

advanced non-small-cell lung cancer receiving carboplatin-basedan.2014.03.017

25] Feyer P, Jordan K. Update and new trends in antiemetic therapy: the continuingneed for novel therapies. Ann Oncol 2010;22:30–8.

26] Vardy J, Chiew KS, Galica J, Pond GR, Tannock IF. Side effects associated withthe use of dexamethasone for prophylaxis of delayed emesis after moderatelyemetogenic chemotherapy. Br J Cancer 2006;94:1011–5.