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 in combination improved the antiemetic effect of ondansetron [24], with dexamethasone. The new agent, palonosetron has granisetron [19], tropisetron [1] and dolasetron [24] in been investigated in two phase III trials in patients re- patients treated with MEC. ceiving 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 5-HT3-receptor antagonists induced by MEC is therefore a single 0.25 mg i.v. dose. No oral dose of palonosetron is currently available. The 5-HT3-receptor antagonists, ondansetron, granise- Granisetron, dolasetron and tropisetron can be given as tron, dolasetron and tropisetron have all been reviewed in single oral doses of 2 mg, 100 mg and 5 mg, respectively. the previous guidelines. There was consensus that no As for ondansetron Beck et al. [4] showed that 8 mg clinically meaningful differences exist between the agents orally twice daily is as effective as 8 mg orally three times for efficacy and toxicity in MEC, but it was recognized daily, but no randomized, blinded studies have investi- that tropisetron has not been as intensively investigated as gated single oral doses of ondansetron in MEC. A study the others [2, 12]. Two large double-blind studies have has shown that a single 16 mg dose of ondansetron given confirmed that granisetron and ondansetron both com- as a suppository is as effective as 8 mg orally twice daily bined with dexamethasone are equally effective in pa- [6]. tients receiving MEC [25, 26], and the latter study, in- The Italian Group for Antiemetic Research, in a ran- cluding more than 1000 patients, also showed that a single domized double-blind trial, investigated a single i.v. dose oral dose of granisetron 2 mg is as effective as a single of dexamethasone 24 mg versus 8 mg versus 8 mg plus 32 mg i.v. dose of ondansetron [26]. 4 mg orally times four. No significant differences were Studies with ondansetron have shown that this agent seen in the prophylaxis of acute emesis in this trial de- can be given as a suppository [6] or as an orally disinte- signed to find differences larger than 15% [20]. The grating tablet [7] with the same effect as conventional oral recommended dose of dexamethasone is therefore 8 mg administration.

Table 2 Doses of 5-HT3-re- 5-HT -receptor antagonist Oral dose Intravenous dose ceptor antagonists 3 Ondansetron 8 mg twice daily 8 mg daily Granisetron 2 mg daily 1 mg daily Dolasetron 100–200 mg daily 1.8 mg/kg daily Tropisetron 5 mg daily 5 mg daily Palonosetron NA 0.25 mg daily 100

Several studies have, as mentioned above, confirmed Other antiemetics that the effect of a 5-HT3-receptor antagonist is improved by the addition of dexamethasone, and this combination is These include benzodiazepines and cannabinoids. The use still considered the standard antiemetic therapy in patients of cannabinoids is restricted by the adverse event profile. receiving MEC. Several additional 5-HT3-receptor an- Lorazepam has, in a randomized, double-blind trial [16], tagonists have also been studied. These include azasetron improved the effect of ondansetron plus dexamethasone [10], ramosetron [23], itasetron [11] palonosetron [8, 13]. in patients with emesis in the previous cycle of MEC, in They have all been included in studies of patients re- spite of treatment with ondansetron plus dexamethasone. ceiving cisplatin, but only palonosetron has been investigated in large phase III comparative trials in patients receiving MEC. NK1-receptor antagonists Palonosetron has a half-life of approximately 40 h and also a higher binding affinity for 5-HT3-receptors than the Two large randomized studies [18, 27] have compared other 5-HT3-receptor antagonists. Gralla et al. [13] com- 3 days of therapy with aprepitant combined with standard pared the effect and toxicity of palonosetron and on- antiemetic therapy (5-HT3-receptor antagonist plus dansetron in a randomized, double-blind phase III trial dexamethasone) versus standard antiemetic therapy alone including 570 patients. Patients received MEC and were in patients receiving cisplatin-based chemotherapy. No randomized to palonosetron 0.25 mg i.v. single dose, or studies have been published to date (April 2004) in pa- palonosetron 0.75 mg i.v. single dose or ondansetron tients receiving MEC. 32 mg i.v. single dose. Concomitant corticosteroid was not permitted. The study included both chemotherapy- naive patients and non-naive patients. Patients were Multiple cycles of MEC stratified for gender and prior chemotherapy experience. In the first 24 h after chemotherapy, palonosetron 0.25 mg A majority of patients receive multiple cycles of che- was significantly superior to ondansetron in preventing motherapy, but only a few trials have addressed additional acute emesis. In another phase III study in 592 patients courses. The conflicting results obtained in these trials receiving MEC, Eisenberg et al. [8] compared palonose- could be due to the different number of cycles followed in tron (single i.v. dose of 0.25 mg versus 0.75 mg) and the studies, the use of an open study design after cycle dolasetron (100 mg i.v., single dose). Approximately one- one, and differences in the statistics used. De Wit et al. third of the patients had received prior chemotherapy and demonstrated that differences in results could be due to only 5% received dexamethasone in combination with analysis based on conditional instead of cumulative palonosetron/dolasetron. No significant differences were probabilities [32]. seen in the acute phase between palonosetron and dola- Three studies prospectively followed patients through setron. Studies comparing palonosetron plus dexametha- six to nine cycles of MEC using a randomized, double- sone with other 5-HT3-receptor antagonists plus dexa- blind design. In the first study 223 patients were followed methasone involving MEC for acute nausea and vomiting through nine cycles of CMF/CEF chemotherapy (total (the recommended antiemetic prophylaxis against acute number of cycles 898). Neither granisetron alone nor emesis) are warranted. prednisolone plus metopimazine was able to maintain antiemetic efficacy [28]. These antiemetic regimens are, however, no longer recommended as a standard for pro- Dopamine D2 receptor antagonists phylaxis of emesis induced by MEC. In another study, Soukop et al. [30] followed 187 women receiving adju- The role of dopamine D2 receptor antagonists in the vant cyclophosphamide-based chemotherapy through six prophylaxis of acute emesis from MEC seems to be cycles. Although ondansetron plus dexamethasone was limited to (1) patients with refractory emesis after previ- superior to dexamethasone plus metoclopramide, the ef- ous antiemetic therapy with a combination of a 5-HT3- fect of both regimens declined during multiple cycles. In a receptor antagonist plus a corticosteroid or (2) patients third randomized, double-blind trial, Sigsgaard et al. [29] who are not suitable for treatment with corticosteroids. compared the effect of ondansetron plus metopimazine Herrstedt et al. have shown that the addition of metopi- with ondansetron plus metopimazine plus prednisolone in mazine 30 mg four times daily to ondansetron reduces the 221 women receiving CMF/CEF chemotherapy and fol- incidence of acute nausea (P=0.006) and vomiting lowed through nine cycles (total of 1462 cycles). In the (P=0.02) compared with ondansetron alone in patients first cycle, the only significant difference observed, be- who received i.v. CMF/CEF/C chemotherapy [17]. In tween the two regimens, was less delayed nausea (days 2– daily clinical practice, dopamine antagonists are also used 5) with the three-drug regimen. Using analysis based on in patients with break-through emesis, but this indication cumulative probabilities, the effect of both antiemetic has not been investigated in a randomized trial. regimens declined through the subsequent cycles. The 101 cumulative emetic protection rate after nine cycles of – The recommended oral dose of ondansetron is 16 mg chemotherapy was 0.75 with the three-drug regimen as (randomized studies have tested the 8 mg twice-daily compared with 0.52 with the two-drug regimen schedule). (P=0.0014). MASCC Level of confidence: high. Level of consensus: high ASCO Level of evidence: I. Grade of recommenda- Conclusion tion: A – The recommended i.v. dose of ondansetron is 8 mg or The standard antiemetic therapy for acute emesis in pa- 0.15 mg/kg as a single dose. tients receiving MEC is a combination of a 5-HT3-re- MASCC Level of confidence: moderate. Level of ceptor antagonist plus dexamethasone. This is important consensus: high not only for protection in the initial 24 h, but the use of ASCO Level of evidence: III. Grade of recommenda- this combination for acute emesis induced by MEC also tion: B decreases the incidence of delayed emesis compared with – The recommended oral dose of granisetron is 2 mg as a less-effective regimens. The new 5-HT3-receptor antag- single dose. onist, palonosetron, used as a single agent, has been in- MASCC Level of confidence: high. Level of consen- vestigated in two phase III trials and is at least as effective sus: high as dolasetron and ondansetron in the first 24 h after MEC. ASCO Level of evidence: I. Grade of recommenda- The effect of palonosetron in combination with dexa- tion: A methasone for acute emesis in MEC should be investi- – The recommended i.v. dose of granisetron is 1 mg or gated. Results of studies with the NK1 receptor antago- 0.01 mg/kg as a single dose. nist, aprepitant, in patients receiving MEC will soon be MASCC Level of confidence: high. Level of consen- available and might change the present recommendations. sus: high Patients with refractory emesis after treatment with ASCO Level of evidence: I. Grade of recommenda- MEC and standard antiemetic prophylaxis might benefit tion: A from the addition of a dopamine receptor antagonist or a – The recommended oral dose of dolasetron is 100 mg as benzodiazepine in the subsequent cycles. No randomized a single dose. trials have demonstrated maintenance of antiemetic effi- MASCC Level of confidence: moderate. Level of cacy during multiple (more than three) cycles of MEC. consensus: high Therefore investigations of multiple cycles of MEC ASCO Level of evidence: II. Grade of recommenda- should be initiated investigating the use of both palono- tion: A setron and aprepitant in this setting. The statements of the – The recommended i.v. dose of dolasetron is 100 mg or Perugia Consensus Conference which took place in 1.8 mg/kg as a single dose. March 2004 are given in the appendix. MASCC Level of confidence: moderate. Level of consensus: high ASCO Level of evidence: II. Grade of recommenda- Appendix: Consensus statements tion: A – The recommended oral dose of tropisetron is 5 mg as a 1. A 5-HT3-receptor antagonist plus dexamethasone is single dose. recommended for prophylaxis of acute nausea and MASCC Level of confidence: low. Level of consen- vomiting in the first course of MEC. sus: high MASCC Level of confidence: high. Level of consen- ASCO Level of evidence: III. Grade of recommenda- sus: high tion: B ASCO Level of evidence: I. Grade of recommenda- – The recommended i.v. dose of tropisetron is 5 mg as a tion: A single dose. 2. There is no difference in the effectiveness of oral or MASCC Level of confidence: moderate. Level of i.v. administration of a 5-HT3-receptor antagonist consensus: high (palonosetron is only available as an i.v. formulation). ASCO Level of evidence: III. Grade of recommenda- MASCC Level of confidence: high. Level of consen- tion: B sus: high – The recommended i.v. dose of palonosetron is 0.25 mg ASCO Level of evidence: I. Grade of recommenda- as a single dose. tion: A MASCC Level of confidence: high. Level of consen- 3. Recommended doses of 5-HT3-receptor antagonists in sus: high MEC (palonosetron is only available as an i.v. for- ASCO Level of evidence: I. Grade of recommenda- mulation). tion: A 102

4. Effectiveness and toxicity of the 5-HT3-receptor an- 6. The antiemetic effect of the standard prophylaxis (5- tagonists. HT3-receptor antagonist plus dexamethasone) declines – There are no clinically relevant differences in the ef- during multiple cycles (more than 3) of MEC. fectiveness of the 5-HT3-receptor antagonists in the MASCC Level of confidence: high. Level of consen- prophylaxis of acute nausea and vomiting when given sus: high according to guidelines in the first cycle of MEC. ASCO Level of evidence: I. Grade of recommenda- MASCC Level of confidence: high. Level of consen- tion: A sus: high 7. A dopamine antagonist can be used as supplement in ASCO Level of evidence: I. Grade of recommenda- the subsequent cycles in patients who experience tion: A nausea/emesis from MEC after treatment with standard – There are no clinically relevant differences in the antiemetic therapy (5-HT3-receptor antagonist plus toxicity of the 5-HT3-receptor antagonists. dexamethasone). MASCC Level of confidence: high. Level of consen- MASCC Level of confidence: moderate. Level of sus: high consensus: high ASCO Level of evidence: I. Grade of recommenda- ASCO Level of evidence: II. Grade of recommendation: A tion: B 8. A benzodiazepine can be used as supplement in the 5. The recommended dose of dexamethasone for pro- subsequent cycles in patients who experience nausea/ phylaxis of acute nausea and vomiting from MEC is emesis from MEC after treatment with standard anti- 8 mg i.v. as a single dose. emetic therapy (5-HT3-receptor antagonist plus dexa- MASCC Level of confidence: moderate. Level of methasone). consensus: high MASCC Level of confidence: moderate. Level of ASCO Level of evidence: II. Grade of recommenda- consensus: moderate tion: B ASCO Level of evidence: II. Grade of recommendation: B

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