Acute emesis: moderately emetogenic chemotherapy

Transcription

1 Support Care Cancer (2005) 13: DOI /s R E V I E W R T I C L E Jørn Herrstedt Jim M. Koeller Fausto Roila Paul J. Hesketh David Warr Cynthia Rittenberg Mario Dicato cute emesis: moderately emetogenic chemotherapy Received: 17 ugust 2004 ccepted: 26 ugust 2004 Published online: 23 November 2004 Springer-Verlag 2004 J. Herrstedt () ) Department of Oncology 54 1, Copenhagen University Hospital, DK-2730 Herlev, Denmark jrhe@herlevhosp.kbhamt.dk Tel.: Fax: J. M. Koeller University of Texas Health Science Center at San ntonio, San ntonio, TX, US F. Roila Policlinico Hospital, Perugia, Italy P. J. Hesketh Caritas St. Elizabeth s Medical Center of oston, oston, M, US D. Warr Princess Margaret Hospital, University of Toronto, Canada C. Rittenberg Rittenberg Oncology Consulting, Metairie, L, US M. Dicato Luxembourg Medical Center, Luxembourg bstract This paper is a review of the recommendations for the prophylaxis of acute emesis induced by moderately emetogenic chemotherapy as concluded at the Perugia Consensus Conference, which took place at the end of March The review focuses on new studies appearing since the last consensus conference in The following issues are addressed: dose and schedule of antiemetics, different groups of antiemetics such as corticosteroids, serotonin (5-HT 3 )-receptor antagonists, dopamine D 2 receptor antagonists, and neurokinin (NK 1 ) receptor antagonists. ntiemetic prophylaxis in patients receiving multiple cycles of moderately emetogenic chemotherapy is also reviewed. Consensus statements are given, including optimal dose and schedule of 5-HT 3 -receptor antagonists and of dexamethasone. The new 5-HT 3 -receptor antagonist, palonosetron, is a reasonable alternative to the well-established agents of this class ondansetron, granisetron, tropisetron and dolasetron. It is concluded that the best prophylaxis in patients receiving moderately emetogenic chemotherapy is still the combination of one of the 5-HT 3 -receptor antagonists and dexamethasone. The results of studies adding a NK 1 -receptor antagonist to this combination are awaited and might change future recommendations. Keywords Serotonin antagonists Dexamethasone nthracycline Cyclophosphamide Chemotherapy ackground The majority of antiemetic studies have focused on patients receiving their first course of chemotherapy with either a cisplatin-based (ly emetogenic) regimen or a cyclophosphamide/anthracycline-based (moderately emetogenic) regimen. Furthermore the observation period in many of these trials was restricted to the initial 24 h following chemotherapy. This means that guidelines have levels of evidence and grades of recommenda-

2 98 tion concerning prophylaxis of acute emesis in chemotherapy-naive patients, but lower levels/grades concerning other aspects of chemotherapy-induced emesis. s for patients receiving moderate emetogenic chemotherapy (MEC), we consequently have a number of studies investigating antiemetic prophylaxis during the first course of cyclophosphamide, methotrexate plus 5-fluorouracil (CMF) or cyclophosphamide, epirubicin plus 5-fluorouracil (CEF/FEC) or doxorubicin/epirubicin plus cyclophosphamide (C/EC) chemotherapy. On the contrary, only a few studies have addressed emesis in patients treated with carboplatin [5] and even fewer studies in those receiving ifosfamide and other kinds of MEC. Focusing only on the first course of chemotherapy also creates the potential risk of overestimating the efficacy of antiemetic prophylaxis in studies compared with the efficacy obtained in daily clinical practice, because patients typically receive multiple courses of chemotherapy. Recent studies have indicated that although antiemetic prophylaxis has been markedly improved by the use of serotonin (5-HT) 3 receptor antagonists, nausea is still the most feared adverse event to chemotherapy [14]. Still, 47% of patients reported acute nausea and 28% acute vomiting after their first course of MEC [15] in spite of optimal evidence-based antiemetic prophylaxis 5-HT 3 - receptor antagonist plus a corticosteroid). Current practice guidelines for prophylaxis of acute emesis induced by MEC The current MSCC [2], SCO [12], SHP [3] and ESMO [9] practice guidelines for prophylaxis of acute emesis following MEC are summarized in Table 1. The recommendations are clear-cut and all agree that a 5-HT 3 - receptor antagonist in combination with a corticosteroid (dexamethasone) is the treatment of choice. The est level of evidence and grade of recommendation applies to cyclophosphamide and anthracycline-based chemotherapy and to a lesser extent carboplatin. Literature search strategy Current guideline references were used as the basis for the selected references up to year Medline search (from 1997 to 2004, 7 March) was conducted of articles using the search terms: acute emesis and chemotherapy. n additional number of Medline searches were completed using the term acute emesis and an antiemetic as the second search term. The antiemetic search terms that were used were ondansetron, granisetron, dolasetron, tropisetron, ramosetron, azasetron, palonosetron, metoclopramide, prochlorperazine, metopimazine, domperidone, dexamethasone, prednisolone, methylprednisolone, prednisone, benzodiazepines, cannabinoids, and aprepitant. Medline searches using the term acute emesis and a chemotherapy agent as the second search term were also done. The chemotherapy terms used were anthracyclines, doxorubicin, epirubicin, cyclophosphamide, carboplatin, and ifosfamide. Finally a search using the same terms and also multiple cycles/courses was carried out. The studies included in the last search were all identified in at least one of the previous searches. This strategy ensured very sensitive, but non-specific results, including from 10 (ifosfamide) to 476 (ondansetron) references in each search. Subsequently each search was manually reviewed, and studies not investigating chemotherapy-induced emesis and those investigating emesis in pediatric populations were excluded. ll the searches were thereafter critically reviewed by at least three of the authors, who identified references to be included. If two or more of these concluded that a reference was important, it was included in the final list of references. ll these references were reviewed, but primarily studies adding new knowledge to the previous guidelines of MSCC, SCO, SHP and ESMO were included in the reference list of this paper. Only randomized studies were included, and with the exception of a few trials only double-blind studies were considered. Overview of the literature The majority of randomized trials followed patients through the first cycle of chemotherapy only. few studies followed patients through multiple cycles of Table 1 Previous consensus guideline recommendations Group Reference Recommendation Confidence/evidence/consensus/grade of recommendation MSCC 4 5-HT 3 -receptor antagonist plus dexamethasone Level of confidence: Level of consensus: SCO 5 5-HT 3 -receptor antagonist plus dexamethasone Level of evidence: I Grade of recommendation: SHP 6 5-HT 3 -receptor antagonist plus dexamethasone Level of evidence: ESMO 7 5-HT 3 -receptor antagonist plus dexamethasone Level of evidence: I Grade of recommendation:

3 99 chemotherapy, and these studies are described separately. Studies in patients receiving multiple-day chemotherapy and studies in patients with refractory emesis or with breakthrough emesis are not discussed here. Since the publication of the present guidelines, studies confirming the optimal doses of 5-HT 3 -receptor antagonists and of dexamethasone have been published. Furthermore two phase III studies with a new 5-HT 3 -receptor antagonist, palonosetron, in patients receiving MEC have recently been published. Dose and schedule Recommended doses of 5-HT 3 -receptor antagonists are given in Table 2. ll the 5-HT 3 -receptor antagonists can be given as a single intravenous (i.v.) dose as prophylaxis of acute emesis. Kaizer et al. [22] showed that a single 16 mg i.v. dose of ondansetron is as effective as 8 mg i.v. followed after 12 h by 8 mg orally. strong indication that 8 mg i.v. is as effective is found in the results from a recent study by the Italian Group for ntiemetic Research [20] in which a complete protection rate in about 90% was seen using a single 8 mg i.v. dose in combination with dexamethasone. The new agent, palonosetron has been investigated in two phase III trials in patients receiving MEC [8, 13]. In both these trials a single i.v. dose of 0.25 mg was as effective as 0.75 mg. The recommended dose of this agent for protection against emesis induced by MEC is therefore a single 0.25 mg i.v. dose. No oral dose of palonosetron is currently available. Granisetron, dolasetron and tropisetron can be given as single oral doses of 2 mg, 100 mg and 5 mg, respectively. s for ondansetron eck et al. [4] showed that 8 mg orally twice daily is as effective as 8 mg orally three times daily, but no randomized, blinded studies have investigated single oral doses of ondansetron in MEC. study has shown that a single 16 mg dose of ondansetron given as a suppository is as effective as 8 mg orally twice daily [6]. The Italian Group for ntiemetic Research, in a randomized double-blind trial, investigated a single i.v. dose of dexamethasone 24 mg versus 8 mg versus 8 mg plus 4 mg orally times four. No significant differences were seen in the prophylaxis of acute emesis in this trial designed to find differences larger than 15% [20]. The recommended dose of dexamethasone is therefore 8 mg i.v. (single dose) although it is unknown if smaller doses are as effective as 8 mg. Corticosteroids The most intensively investigated corticosteroid is dexamethasone, but no studies have actually indicated that there is a difference in antiemetic effect or toxicity between the various corticosteroids. s described in the previous guidelines [2, 12], dexamethasone has been consistently equal or superior to metoclopramide and equal to 5-HT 3 -receptor antagonists such as ondansetron [21] and granisetron [19] in patients receiving cyclophosphamide- or anthracycline-based chemotherapy. Two randomized studies have indicated that dexamethasone plus prochlorperazine [31] or prednisolone plus metopimazine [28] is inferior to granisetron in patients receiving MEC. In the first study chemotherapy also included cisplatin (20 50 mg/m 2 ) and in the second study prednisolone was given in a dose equal to only 50% of the recently established optimal dose of dexamethasone [20]. Dexamethasone has in randomized, double-blind trials improved the antiemetic effect of ondansetron [24], granisetron [19], tropisetron [1] and dolasetron [24] in patients treated with MEC. 5-HT 3 -receptor antagonists The 5-HT 3 -receptor antagonists, ondansetron, granisetron, dolasetron and tropisetron have all been reviewed in the previous guidelines. There was consensus that no clinically meaningful differences exist between the agents for efficacy and toxicity in MEC, but it was recognized that tropisetron has not been as intensively investigated as the others [2, 12]. Two large double-blind studies have confirmed that granisetron and ondansetron both combined with dexamethasone are equally effective in patients receiving MEC [25, 26], and the latter study, including more than 1000 patients, also showed that a single oral dose of granisetron 2 mg is as effective as a single 32 mg i.v. dose of ondansetron [26]. Studies with ondansetron have shown that this agent can be given as a suppository [6] or as an orally disintegrating tablet [7] with the same effect as conventional oral administration. Table 2 Doses of 5-HT 3 -receptor antagonists 5-HT 3 -receptor antagonist Oral dose Intravenous dose Ondansetron 8 mg twice daily 8 mg daily Granisetron 2 mg daily 1 mg daily Dolasetron mg daily 1.8 mg/kg daily Tropisetron 5 mg daily 5 mg daily Palonosetron N 0.25 mg daily

4 100 Several studies have, as mentioned above, confirmed that the effect of a 5-HT 3 -receptor antagonist is improved by the addition of dexamethasone, and this combination is still considered the standard antiemetic therapy in patients receiving MEC. Several additional 5-HT 3 -receptor antagonists have also been studied. These include azasetron [10], ramosetron [23], itasetron [11] palonosetron [8, 13]. They have all been included in studies of patients receiving cisplatin, but only palonosetron has been investigated in large phase III comparative trials in patients receiving MEC. Palonosetron has a half-life of approximately 40 h and also a er binding affinity for 5-HT 3 -receptors than the other 5-HT 3 -receptor antagonists. Gralla et al. [13] compared the effect and toxicity of palonosetron and ondansetron in a randomized, double-blind phase III trial including 570 patients. Patients received MEC and were randomized to palonosetron 0.25 mg i.v. single dose, or palonosetron 0.75 mg i.v. single dose or ondansetron 32 mg i.v. single dose. Concomitant corticosteroid was not permitted. The study included both chemotherapynaive patients and non-naive patients. Patients were stratified for gender and prior chemotherapy experience. In the first 24 h after chemotherapy, palonosetron 0.25 mg was significantly superior to ondansetron in preventing acute emesis. In another phase III study in 592 patients receiving MEC, Eisenberg et al. [8] compared palonosetron (single i.v. dose of 0.25 mg versus 0.75 mg) and dolasetron (100 mg i.v., single dose). pproximately onethird of the patients had received prior chemotherapy and only 5% received dexamethasone in combination with palonosetron/dolasetron. No significant differences were seen in the acute phase between palonosetron and dolasetron. Studies comparing palonosetron plus dexamethasone with other 5-HT 3 -receptor antagonists plus dexamethasone involving MEC for acute nausea and vomiting (the recommended antiemetic prophylaxis against acute emesis) are warranted. Dopamine D 2 receptor antagonists The role of dopamine D 2 receptor antagonists in the prophylaxis of acute emesis from MEC seems to be limited to (1) patients with refractory emesis after previous antiemetic therapy with a combination of a 5-HT 3 - receptor antagonist plus a corticosteroid or (2) patients who are not suitable for treatment with corticosteroids. Herrstedt et al. have shown that the addition of metopimazine 30 mg four times daily to ondansetron reduces the incidence of acute nausea (P=0.006) and vomiting (P=0.02) compared with ondansetron alone in patients who received i.v. CMF/CEF/C chemotherapy [17]. In daily clinical practice, dopamine antagonists are also used in patients with break-through emesis, but this indication has not been investigated in a randomized trial. Other antiemetics These include benzodiazepines and cannabinoids. The use of cannabinoids is restricted by the adverse event profile. Lorazepam has, in a randomized, double-blind trial [16], improved the effect of ondansetron plus dexamethasone in patients with emesis in the previous cycle of MEC, in spite of treatment with ondansetron plus dexamethasone. NK 1 -receptor antagonists Two large randomized studies [18, 27] have compared 3 days of therapy with aprepitant combined with standard antiemetic therapy (5-HT 3 -receptor antagonist plus dexamethasone) versus standard antiemetic therapy alone in patients receiving cisplatin-based chemotherapy. No studies have been published to date (pril 2004) in patients receiving MEC. Multiple cycles of MEC majority of patients receive multiple cycles of chemotherapy, but only a few trials have addressed additional courses. The conflicting results obtained in these trials could be due to the different number of cycles followed in the studies, the use of an open study design after cycle one, and differences in the statistics used. De Wit et al. demonstrated that differences in results could be due to analysis based on conditional instead of cumulative probabilities [32]. Three studies prospectively followed patients through six to nine cycles of MEC using a randomized, doubleblind design. In the first study 223 patients were followed through nine cycles of CMF/CEF chemotherapy (total number of cycles 898). Neither granisetron alone nor prednisolone plus metopimazine was able to maintain antiemetic efficacy [28]. These antiemetic regimens are, however, no longer recommended as a standard for prophylaxis of emesis induced by MEC. In another study, Soukop et al. [30] followed 187 women receiving adjuvant cyclophosphamide-based chemotherapy through six cycles. lthough ondansetron plus dexamethasone was superior to dexamethasone plus metoclopramide, the effect of both regimens declined during multiple cycles. In a third randomized, double-blind trial, Sigsgaard et al. [29] compared the effect of ondansetron plus metopimazine with ondansetron plus metopimazine plus prednisolone in 221 women receiving CMF/CEF chemotherapy and followed through nine cycles (total of 1462 cycles). In the first cycle, the only significant difference observed, between the two regimens, was less delayed nausea (days 2 5) with the three-drug regimen. Using analysis based on cumulative probabilities, the effect of both antiemetic regimens declined through the subsequent cycles. The

5 101 cumulative emetic protection rate after nine cycles of chemotherapy was 0.75 with the three-drug regimen as compared with 0.52 with the two-drug regimen (P=0.0014). Conclusion The standard antiemetic therapy for acute emesis in patients receiving MEC is a combination of a 5-HT 3 -receptor antagonist plus dexamethasone. This is important not only for protection in the initial 24 h, but the use of this combination for acute emesis induced by MEC also decreases the incidence of delayed emesis compared with less-effective regimens. The new 5-HT 3 -receptor antagonist, palonosetron, used as a single agent, has been investigated in two phase III trials and is at least as effective as dolasetron and ondansetron in the first 24 h after MEC. The effect of palonosetron in combination with dexamethasone for acute emesis in MEC should be investigated. Results of studies with the NK 1 receptor antagonist, aprepitant, in patients receiving MEC will soon be available and might change the present recommendations. Patients with refractory emesis after treatment with MEC and standard antiemetic prophylaxis might benefit from the addition of a dopamine receptor antagonist or a benzodiazepine in the subsequent cycles. No randomized trials have demonstrated maintenance of antiemetic efficacy during multiple (more than three) cycles of MEC. Therefore investigations of multiple cycles of MEC should be initiated investigating the use of both palonosetron and aprepitant in this setting. The statements of the Perugia Consensus Conference which took place in March 2004 are given in the appendix. ppendix: Consensus statements 1. 5-HT 3 -receptor antagonist plus dexamethasone is recommended for prophylaxis of acute nausea and vomiting in the first course of MEC. MSCC Level of confidence:. Level of consensus: SCO Level of evidence: I. Grade of recommendation: 2. There is no difference in the effectiveness of oral or i.v. administration of a 5-HT 3 -receptor antagonist (palonosetron is only available as an i.v. formulation). MSCC Level of confidence:. Level of consensus: SCO Level of evidence: I. Grade of recommendation: 3. Recommended doses of 5-HT 3 -receptor antagonists in MEC (palonosetron is only available as an i.v. formulation). The recommended oral dose of ondansetron is 16 mg (randomized studies have tested the 8 mg twice-daily schedule). MSCC Level of confidence:. Level of consensus: SCO Level of evidence: I. Grade of recommendation: The recommended i.v. dose of ondansetron is 8 mg or 0.15 mg/kg as a single dose. MSCC Level of confidence: moderate. Level of consensus: SCO Level of evidence: III. Grade of recommendation: The recommended oral dose of granisetron is 2 mg as a single dose. MSCC Level of confidence:. Level of consensus: SCO Level of evidence: I. Grade of recommendation: The recommended i.v. dose of granisetron is 1 mg or 0.01 mg/kg as a single dose. MSCC Level of confidence:. Level of consensus: SCO Level of evidence: I. Grade of recommendation: The recommended oral dose of dolasetron is 100 mg as a single dose. MSCC Level of confidence: moderate. Level of consensus: SCO Level of evidence: II. Grade of recommendation: The recommended i.v. dose of dolasetron is 100 mg or 1.8 mg/kg as a single dose. MSCC Level of confidence: moderate. Level of consensus: SCO Level of evidence: II. Grade of recommendation: The recommended oral dose of tropisetron is 5 mg as a single dose. MSCC Level of confidence: low. Level of consensus: SCO Level of evidence: III. Grade of recommendation: The recommended i.v. dose of tropisetron is 5 mg as a single dose. MSCC Level of confidence: moderate. Level of consensus: SCO Level of evidence: III. Grade of recommendation: The recommended i.v. dose of palonosetron is 0.25 mg as a single dose. MSCC Level of confidence:. Level of consensus: SCO Level of evidence: I. Grade of recommendation:

6 Effectiveness and toxicity of the 5-HT 3 -receptor antagonists. There are no clinically relevant differences in the effectiveness of the 5-HT 3 -receptor antagonists in the prophylaxis of acute nausea and vomiting when given according to guidelines in the first cycle of MEC. MSCC Level of confidence:. Level of consensus: SCO Level of evidence: I. Grade of recommendation: There are no clinically relevant differences in the toxicity of the 5-HT 3 -receptor antagonists. MSCC Level of confidence:. Level of consensus: SCO Level of evidence: I. Grade of recommendation: 5. The recommended dose of dexamethasone for prophylaxis of acute nausea and vomiting from MEC is 8 mg i.v. as a single dose. MSCC Level of confidence: moderate. Level of consensus: SCO Level of evidence: II. Grade of recommendation: 6. The antiemetic effect of the standard prophylaxis (5- HT 3 -receptor antagonist plus dexamethasone) declines during multiple cycles (more than 3) of MEC. MSCC Level of confidence:. Level of consensus: SCO Level of evidence: I. Grade of recommendation: 7. dopamine antagonist can be used as supplement in the subsequent cycles in patients who experience nausea/emesis from MEC after treatment with standard antiemetic therapy (5-HT 3 -receptor antagonist plus dexamethasone). MSCC Level of confidence: moderate. Level of consensus: SCO Level of evidence: II. Grade of recommendation: 8. benzodiazepine can be used as supplement in the subsequent cycles in patients who experience nausea/ emesis from MEC after treatment with standard antiemetic therapy (5-HT 3 -receptor antagonist plus dexamethasone). MSCC Level of confidence: moderate. Level of consensus: moderate SCO Level of evidence: II. Grade of recommendation: References 1. dams M, Soukop M, arley V, et al (1995) Tropisetron alone or in combination with dexamethasone for the prevention and treatment of emesis induced by non-cisplatin chemotherapy: a randomized trial. nticancer Drugs 6: ntiemetic Subcommittee of the Multinational ssociation of Supportive Care in Cancer (MSCC) (1998) Prevention of chemotherapy- and radiotherapy-induced emesis: results of the Perugia Consensus Conference. nn Oncol 9: SHP Commission on Therapeutics (1999) SHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. m J Health Syst Pharm 56: eck TM, York M, Chang, et al (1997) Oral ondansetron 8 mg twice daily is as effective as 8 mg three times daily in the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. S3-376 Study Group. Cancer Invest 15: Du ois, McKenna CJ, ndersson H, Lahousen M, Kitchener H, Pinter T, Capstick V, Wilkinson JR (1997) randomised, double-blind, parallelgroup study to compare the efficacy and safety of ondansetron (GR38032F) plus dexamethasone with metoclopramide plus dexamethasone in the prophylaxis of nausea and emesis induced by carboplatin chemotherapy. Oncology 54: Davidson NG, Paska W, Van elle S, Goedhals L, McQuade, McRae J (1997) Ondansetron suppository: a randomised, double-blind, double-dummy, parallel-group comparison with oral ondansetron for the prevention of cyclophosphamide-induced emesis and nausea. The Ondansetron Suppository Emesis Study Group. Oncology 54: Davidson N, Rapoport, Erikstein, et al (1999) Comparison of an orally disintegrating ondansetron tablet with the conventional ondansetron tablet for cyclophosphamide-induced emesis in cancer patients: a multicenter, doublemasked study. Ondansetron Orally Disintegrating Tablet Emesis Study Group. Clin Ther 21: Eisenberg P, Figueroa-Vadillo J, Zamora R, et al (2003) Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT 3 -receptor antagonist. Cancer 98: ESMO Guidelines Task Force (2001) ESMO recommendations for prophylaxis of chemotherapy-induced nausea and vomiting. nn Oncol 12: Fujii M, Kanke M, rai Y, et al (2000) randomized crossover comparison of azasetron alone and azasetron plus dexamethasone for the prevention of nausea and vomiting by chemotherapy including cisplatin. Gan To Kagaku Ryoho 27: Goldschmidt H, Salwender H, Egerer G, Kempe R, Voigt T (1997) Comparison of oral itasetron with oral ondansetron: results of a double-blind, active-controlled phase II study in chemotherapy-naive patients receiving moderately emetogenic chemotherapy. nticancer Drugs 8: Gralla RJ, Osoba D, Kris MG, et al (1999) Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. J Clin Oncol 17:

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