Acute Emesis: Moderately Emetogenic Chemotherapy

Support Care Cancer (2005) 13:97–103 DOI 10.1007/s00520-004-0701-7 REVIEW ARTICLE Jørn Herrstedt Acute emesis: Jim M. Koeller Fausto Roila moderately emetogenic chemotherapy Paul J. Hesketh David Warr Cynthia Rittenberg Mario Dicato Received: 17 August 2004 Abstract This paper is a review of motherapy is still the combination of Accepted: 26 August 2004 the recommendations for the pro- one of the 5-HT3-receptor antagonists Published online: 23 November 2004 phylaxis of acute emesis induced by and dexamethasone. The results of Springer-Verlag 2004 moderately emetogenic chemothera- studies adding a NK1-receptor an- J. Herrstedt ()) py as concluded at the Perugia Con- tagonist to this combination are Department of Oncology 54 B1, sensus Conference, which took place awaited and might change future Copenhagen University Hospital, at the end of March 2004. The review recommendations. DK-2730 Herlev, Denmark focuses on new studies appearing e-mail: [email protected] since the last consensus conference in Keywords Serotonin antagonists · Tel.: +45-4488-4785 Fax: +45-4453-3076 1997. The following issues are ad- Dexamethasone · Anthracycline · dressed: dose and schedule of Cyclophosphamide · Chemotherapy J. M. Koeller antiemetics, different groups of University of Texas Health Science Center antiemetics such as corticosteroids, at San Antonio, San Antonio, TX, USA serotonin (5-HT3)-receptor antagonists, dopamine D2 receptor antago- F. Roila nists, and neurokinin (NK1) receptor Policlinico Hospital, antagonists. Antiemetic prophylaxis Perugia, Italy in patients receiving multiple cycles P. J. Hesketh of moderately emetogenic chemo- Caritas St. Elizabeth’s Medical Center therapy is also reviewed. Consensus of Boston, statements are given, including opti- Boston, MA, USA mal dose and schedule of 5-HT3-re- D. Warr ceptor antagonists and of dexameth- Princess Margaret Hospital, asone. The new 5-HT3-receptor an- University of Toronto, tagonist, palonosetron, is a reason- Canada able alternative to the well-estab- C. Rittenberg lished agents of this class—on- Rittenberg Oncology Consulting, dansetron, granisetron, tropisetron Metairie, LA, USA and dolasetron. It is concluded that M. Dicato the best prophylaxis in patients re- Luxembourg Medical Center, ceiving moderately emetogenic che- Luxembourg Background cyclophosphamide/anthracycline-based (moderately emetogenic) regimen. Furthermore the observation period in The majority of antiemetic studies have focused on pa- many of these trials was restricted to the initial 24 h fol- tients receiving their first course of chemotherapy with lowing chemotherapy. This means that guidelines have either a cisplatin-based (highly emetogenic) regimen or a high levels of evidence and high grades of recommenda- 98 tion concerning prophylaxis of acute emesis in chemo- Literature search strategy therapy-naive patients, but lower levels/grades concerning other aspects of chemotherapy-induced emesis. As for Current guideline references were used as the basis for the patients receiving moderate emetogenic chemotherapy selected references up to year 1997. A Medline search (MEC), we consequently have a number of studies in- (from 1997 to 2004, 7 March) was conducted of articles vestigating antiemetic prophylaxis during the first course using the search terms: “acute emesis” and “chemother- of cyclophosphamide, methotrexate plus 5-fluorouracil apy”. An additional number of Medline searches were (CMF) or cyclophosphamide, epirubicin plus 5-fluoro- completed using the term “acute emesis” and an anti- uracil (CEF/FEC) or doxorubicin/epirubicin plus cyclo- emetic as the second search term. The antiemetic search phosphamide (AC/EC) chemotherapy. On the contrary, terms that were used were ondansetron, granisetron, do- only a few studies have addressed emesis in patients lasetron, tropisetron, ramosetron, azasetron, palonosetron, treated with carboplatin [5] and even fewer studies in metoclopramide, prochlorperazine, metopimazine, dom- those receiving ifosfamide and other kinds of MEC. Fo- peridone, dexamethasone, prednisolone, methylpredniso- cusing only on the first course of chemotherapy also cre- lone, prednisone, benzodiazepines, cannabinoids, and ates the potential risk of overestimating the efficacy of aprepitant. Medline searches using the term “acute eme- antiemetic prophylaxis in studies compared with the effi- sis” and a chemotherapy agent as the second search term cacy obtained in daily clinical practice, because patients were also done. The chemotherapy terms used were an- typically receive multiple courses of chemotherapy. thracyclines, doxorubicin, epirubicin, cyclophosphamide, Recent studies have indicated that although antiemetic carboplatin, and ifosfamide. Finally a search using the prophylaxis has been markedly improved by the use of same terms and also multiple cycles/courses was carried serotonin (5-HT)3 receptor antagonists, nausea is still the out. The studies included in the last search were all most feared adverse event to chemotherapy [14]. Still, identified in at least one of the previous searches. This 47% of patients reported acute nausea and 28% acute strategy ensured very sensitive, but non-specific results, vomiting after their first course of MEC [15] in spite of including from 10 (ifosfamide) to 476 (ondansetron) ref- optimal evidence-based antiemetic prophylaxis 5-HT3- erences in each search. Subsequently each search was receptor antagonist plus a corticosteroid). manually reviewed, and studies not investigating chemotherapy-induced emesis and those investigating emesis in pediatric populations were excluded. All the searches Current practice guidelines for prophylaxis were thereafter critically reviewed by at least three of the of acute emesis induced by MEC authors, who identified references to be included. If two or more of these concluded that a reference was impor- The current MASCC [2], ASCO [12], ASHP [3] and tant, it was included in the final list of references. All ESMO [9] practice guidelines for prophylaxis of acute these references were reviewed, but primarily studies emesis following MEC are summarized in Table 1. The adding new knowledge to the previous guidelines of recommendations are clear-cut and all agree that a 5-HT3- MASCC, ASCO, ASHP and ESMO were included in the receptor antagonist in combination with a corticosteroid reference list of this paper. Only randomized studies were (dexamethasone) is the treatment of choice. The highest included, and with the exception of a few trials only level of evidence and grade of recommendation applies to double-blind studies were considered. cyclophosphamide and anthracycline-based chemotherapy and to a lesser extent carboplatin. Overview of the literature The majority of randomized trials followed patients through the first cycle of chemotherapy only. A few studies followed patients through multiple cycles of Table 1 Previous consensus guideline recommendations Group Reference Recommendation Confidence/evidence/consensus/grade of recommendation MASCC 4 5-HT3-receptor antagonist plus dexamethasone Level of confidence: high Level of consensus: high ASCO 5 5-HT3-receptor antagonist plus dexamethasone Level of evidence: I Grade of recommendation: A ASHP 6 5-HT3-receptor antagonist plus dexamethasone Level of evidence: A ESMO 7 5-HT3-receptor antagonist plus dexamethasone Level of evidence: I Grade of recommendation: A 99 chemotherapy, and these studies are described separately. i.v. (single dose) although it is unknown if smaller doses Studies in patients receiving multiple-day chemotherapy are as effective as 8 mg. and studies in patients with refractory emesis or with breakthrough emesis are not discussed here. Since the publication of the present guidelines, studies Corticosteroids confirming the optimal doses of 5-HT3-receptor antagonists and of dexamethasone have been published. Fur- The most intensively investigated corticosteroid is dexa- thermore two phase III studies with a new 5-HT3-receptor methasone, but no studies have actually indicated that antagonist, palonosetron, in patients receiving MEC have there is a difference in antiemetic effect or toxicity be- recently been published. tween the various corticosteroids. As described in the previous guidelines [2, 12], dexamethasone has been consistently equal or superior to metoclopramide and Dose and schedule equal to 5-HT3 -receptor antagonists such as ondansetron [21] and granisetron [19] in patients receiving cyclo- Recommended doses of 5-HT3-receptor antagonists are phosphamide- or anthracycline-based chemotherapy. Two given in Table 2. All the 5-HT3-receptor antagonists can randomized studies have indicated that dexamethasone be given as a single intravenous (i.v.) dose as prophylaxis plus prochlorperazine [31] or prednisolone plus metopi- of acute emesis. Kaizer et al. [22] showed that a single mazine [28] is inferior to granisetron in patients receiving 16 mg i.v. dose of ondansetron is as effective as 8 mg i.v. MEC. In the first study chemotherapy also included cis- followed after 12 h by 8 mg orally. A strong indication platin (20–50 mg/m2) and in the second study predniso- that 8 mg i.v. is as effective is found in the results from a lone was given in a dose equal to only 50% of the recently recent study by the Italian Group for Antiemetic Research established optimal dose of dexamethasone [20]. [20] in which a complete protection rate in about 90% Dexamethasone has in randomized, double-blind trials was seen using a single 8 mg i.v. dose

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