Comparative review of 5-HT3 receptor antagonists in the treatment of acute chemotherapy-induced nausea and vomiting

Since their introduction, 5-HT3 receptor antagonists have become the agents of choice in the prevention of acute chemotherapy-induced nausea and vomiting and are generally superior to high-dose metoclopramide regimens. The availability of four different agents (ondansetron, granisetron, dolasetron, and tropisetron) within this class has prompted investigations into potential differences between the drugs, which appear to be few. More importantly, the results of recently conducted randomized comparative trials in patients receiving moderately or highly emetogenic chemotherapy have demonstrated similar efficacy. Although study designs and patient populations differed, seven large comparative trials in patients receiving highly emetogenic chemotherapy reported no significant differences in complete or complete plus major response rates among the agents. Similar results were generally reported in trials evaluating patients receiving moderately emetogenic chemotherapy. The safety and tolerability of these agents also appear to be similar. The most common adverse events include headache, gastrointestinal effects, lightheadedness, and sedation. All agents are available in both intravenous and oral dosage forms and may be administered as a single dose.     

Neurokinin-1 receptor antagonists for chemotherapy-induced nausea and vomiting: a systematic review

Background The addition of neurokinin-1 receptor (NK1R) antagonists to antiemetic regimens has substantially reduced chemotherapy-induced nausea and vomiting (CINV). We sought to systematically review the overall impact of NK1R antagonists on CINV prevention. Methods We systematically searched the MEDLINE, EMBASE, and CENTRAL databases, and meeting proceedings for randomized controlled trials (RCTs) that evaluated NK1R antagonists plus standard antiemetic therapy for CINV prevention. Complete response (CR) to therapy was defined as the absence of emesis and the absence of rescue therapy. The endpoints were defined as CR in the overall phase (during the first 120 hours of chemotherapy), CR in the acute phase (first 24 hours), and the delayed phase (24-120 hours) after chemotherapy, nausea, and toxicity. Subgroup analyses evaluated the type of NK1R antagonist used, the emetogenic potential of the chemotherapy regimen, and prolonged use of 5-HT3 (serotonin) receptor antagonists, a class of standard antiemetic agents. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates and publication bias were two-sided. Results Seventeen trials (8740 patients) were included in this analysis. NK1R antagonists increased the CR rate in the overall phase from 54% to 72% (OR = 0.51, 95% CI = 0.46 to 0.57, P < .001). CR and nausea were improved in all phases and subgroups. The expected side effects from NK1R antagonists did not statistically significantly differ from previous reports; however, this analysis suggests that the incidence of severe infection increased from 2% to 6% in the NK1R antagonist group (three RCTs with a total of 1480 patients; OR = 3.10; 95% CI = 1.69 to 5.67, P < .001). Conclusions NK1R antagonists increased CINV control in the acute, delayed, and overall phases. They are effective for both moderately and highly emetogenic chemotherapy regimens. Their use might be associated with increased infection rates; however, additional appraisal of specific data from RCTs is needed.     

重复使用5-HT3受体拮抗剂预防多日化疗相关性恶心呕吐的疗效和安全性分析

  目的  探讨重复使用第一代5-HT3受体拮抗剂（5-HT3RA）托烷司琼与第二代5-HT3RA帕洛诺司琼预防多日高度催吐风险化疗所致恶心和呕吐（chemotherapy-induced nausea and vomiting,CINV）的疗效和安全性。  方法  在接受含有高度催吐风险药物连续多日化疗的患者中,采用随机、交叉自身对照的方法分组,A方案组为:在第1周期化疗中,帕洛诺司琼0.25 mg,静脉滴注,d1、d3（必要时d5）。地塞米松（DXM）10 mg,静脉滴注,d1;5 mg,静脉滴注,d2~d5。第2周期为托烷司琼5 mg,静脉滴注,d1~d3（必要时d4、d5）;DXM用法同前。B方案组的止吐方案为第1周期使用托烷司琼,第2周期使用帕洛诺司琼（剂量、用法均同A方案组）。将A方案组第1个周期和B方案组第2个周期的患者归为帕洛诺司琼组,A方案第2个周期和B方案组第1个周期的患者归为托烷司琼组,比较帕洛诺司琼与托烷司琼预防CINV的疗效和不良反应。  结果  共计入组91例患者。在d3至d5,帕洛诺司琼组每天恶心发生率分别为28.6%、30.8%和24.2%,托烷司琼组分别为42.8%、47.3%和39.6%,差异均有统计学意义（均P < 0.05）;在d4至d6,帕洛诺司琼组每天呕吐发生率分别为28.6%、18.7%和5.5%,托烷司琼组则为42.9%、34.1%和14.3%,差异均有统计学意义（均P < 0.05）;按时间段分析,帕洛诺司琼组在d4~5、d6~7和全程（d1~7）恶心和呕吐发生率均显著低于托烷司琼组（均P < 0.05）。帕洛诺司琼组全程（d1~7）解救药使用率为13.2%,低于托烷司琼组的24.2%,但差异无统计学意义（P=0.057）。帕洛诺司琼组与托烷司琼组的止吐药物相关性不良反应发生率的差异均无统计学意义（均P > 0.05）。  结论  重复使用帕洛诺司琼预防持续多日高度催吐风险化疗相关的延迟性恶心呕吐的疗效优于托烷司琼,两者的安全性良好。      

The development of a protocol for the use of 5-HT3 antagonists in chemotherapy-induced nausea and vomiting

The purpose of this study was to evaluate the effectiveness of three 5–HT₃ antagonists in routine clinical practice. The ultimate aim was to develop an antiemetic protocol, selecting a single 5–HT₃ antagonist. Each of the drugs was studied for a 4–month period and data was collected from patients on nausea, vomiting (both acute and delayed) and side-effects by means of a diary card. A total of 274 patients were enrolled into the study.Success rates for acute emesis seen over the study period were in excess of 90%. There were no statistically significant differences between any of the three drugs investigated with respect to both acute and delayed nausea and vomiting. Similarly, there was no difference between the three groups for the incidence of constipation, diarrhoea and headache.Granisetron demonstrated a lesser deviation from the protocol in respect of the number of intravenous doses given to patients.The study allowed an effective 5–HT₃ antagonist protocol to be developed for use in the management of nausea and vomiting in cancer patients.     

Comparative efficacy and safety of palonosetron with the first 5-HT3 receptor antagonists for the chemotherapy-induced nausea and vomiting: a meta-analysis

JIN Y., SUN W., GU D., YANG J., XU Z. & CHEN J. (2013) European Journal of Cancer Care 22 , 41–50 Comparative efficacy and safety of palonosetron with the first 5-HT3 receptor antagonists for the chemotherapy-induced nausea and vomiting: a meta-analysis A number of studies have reported the difference between the 5-HT3 receptor antagonists and palonosetron in preventing the chemotherapy-induced nausea and vomiting (CINV). Through analysing the efficacy and safety in palonosetron-treated patients, it can provide evidence for palonosetron administration. We identified randomised controlled clinical trials comparing palonosetron with the first-generation 5-HT3 receptor antagonists in the prevention of CINV in cancer patients. Nine studies investigated the outcomes in a total of 3463 cases. Compared with the first-generation 5-HT3 receptor antagonists, the cumulative incidences of emesis were significantly reduced in the patients treated with palonosetron (0.25 mg i.v.) on the first day [relative risk (RR) = 1.11, 95% confidence interval (CI): 1.05–1.17], from 2 to 5 days (RR = 1.26, 95% CI: 1.16–1.36) and the overall five days (RR = 1.23, 95% CI: 1.13–1.34). Regarding the drug safety, there was no significant difference between palonosetron-treated group and the first-generation 5-HT3 receptor antagonists-treated group. Results from the analysis suggest that palonosetron is highly effective in preventing nausea and vomiting in the days after administration of moderately or highly emetogenic chemotherapy agents.     

阿瑞匹坦联合5-HT3受体拮抗剂和地塞米松预防化疗相关性恶心和呕吐的Meta分析

目的:采用Meta分析方法对阿瑞匹坦联合5-HT3 受体拮抗剂和地塞米松预防化疗相关性恶心和呕吐进行系统评价。方法:检索Pubmed、EMbase、Cochrane Library、中国知网CNKI全文数据库、维普数据库、万方数据库和中国生物医学文献数据库,查找2003年1月至2013年12月公开发表的研究阿瑞匹坦联合5-HT3受体拮抗剂和地塞米松预防化疗相关性恶心和呕吐的临床随机对照试验。按照纳入与排除标准选择文献,质量评估,资料提取,采用RevMan 5.2 软件进行Meta分析。结果:共纳入12篇英文RCT文献,均为高质量研究。Meta分析结果显示,阿瑞匹坦联合5-HT3受体拮抗剂、地塞米松治疗（三联治疗）在预防高、中度致吐性化疗相关性恶心和呕吐的总体完全缓解率［OR=1.91,95%CI（1.68,2.17）,P<0.00001］、急性完全缓解率［OR=1.89,95%CI（1.48,2.42）,P<0.00001］、迟发性完全缓解率［OR=2.05,95%CI（1.68,2.51）,P<0.00001］明显高于5-HT3受体拮抗剂、地塞米松治疗（二联治疗）,两组差异有统计学意义。结论:阿瑞匹坦可以显著提高高、中度致吐性化疗的总体、急性和迟发性恶心和呕吐完全缓解率,尤其是在提高迟发性恶心和呕吐完全缓解率更为明显。     

5-HT(3)-receptor antagonists for the treatment of nausea and vomiting: a reappraisal of their side-effect profile

Nausea and vomiting can cause considerable distress and discomfort to patients undergoing chemotherapy, radiotherapy, or surgery. Several classes of antiemetic agents exist to combat these side effects, though the 5-HT(3)-receptor antagonists have become the first-line treatment choice for many cancer patients and are considered the "gold standard" in antiemetic therapy. Compared with the older generation antiemetic drugs, 5-HT(3)-receptor antagonists are effective, well tolerated, and associated with few side effects. However, emerging differences among these agents suggest that the incidence and/or intensity of adverse events should not be regarded as a class effect. The side-effect profile of any supportive care therapy is particularly important in certain subgroups of patients, including pediatric patients and the elderly, as well as those suffering comorbid conditions, such as cardiovascular disease and renal or hepatic impairment. Indeed, dolasetron is associated with cardiovascular effects, and thus, should be used with extreme caution in patients who suffer from or may develop prolongation of cardiac conduction intervals. Ondansetron, on the other hand, is associated with a greater incidence of central nervous system side effects than either dolasetron or ondansetron, and pharmacokinetic parameters are affected in patients with hepatic impairment, thereby requiring dose adjustments. Clinicians are encouraged to evaluate patients on an individual basis when choosing which 5-HT(3)-receptor antagonist to prescribe.     

5-HT(3)-receptor antagonists in the management of nausea and vomiting in cancer and cancer treatment

The 5-HT(3)-receptor antagonists, considered as 'gold standard' therapy for cancer patients, are generally perceived to have similar efficacy and safety profiles, andmost antiemetic guidelines do not distinguish between agents. However, important pharmacological differences exist between agents, which may translate into potential benefits for some patients. In particular, 5-HT(3)-receptor antagonists vary in the nature of their receptor antagonism and plasma half-lives, possibly leading to differences in duration of action. Agents with a longer duration of action provide antiemetic protection throughout the acute emetic period (24 h) with a single daily dose, whereas shorter-acting agents, e.g. ondansetron, may require multiple dosing for full efficacy. Differences also exist between agents in their hepatic metabolism and cardiovascular safety, which may present particular problems for elderly patients who often receive additional medications for comorbid conditions, increasing the risk of drug-drug interaction. Recent antiemetic guidelines from the National Comprehensive Cancer Network recommend preferential use of palonosetron for moderately emetogenic chemotherapy; however, this agent is newly approved and key clinical questions remain unanswered by clinical trial data. Selection of an appropriate 5-HT(3)-receptor antagonist should be based on proven efficacy and safety, as well as on the individual characteristics of the patient.     

Role of dexamethasone dosage in combination with 5-HT3 antagonists for prophylaxis of acute chemotherapy-induced nausea and vomiting

Dexamethasone (20 mg) or its equivalent in combination with 5-HT3 antagonists appears to be the gold-standard dose for antiemetic prophylaxis. Additional to concerns about the use of corticosteroids with respect to enhanced tumour growth or impaired killing of the tumour cells, there is evidence that high-dosage dexamethasone impairs the control of delayed nausea and emesis, whereas lower doses appear more beneficial. To come closer to the most adequate dose, we started a prospective, single-blind, randomized trial investigating additional dosage of 8 or 20 mg dexamethasone to tropisetron (Navoban), a 5-HT3 receptor antagonist, in cis-platinum-containing chemotherapy. After an interim analysis of 121 courses of chemotherapy in 69 patients, we have been unable to detect major differences between both treatment alternatives. High-dose dexamethasone (20 mg) had no advantage over medium-dose dexamethasone with respect to objective and subjective parameters of acute and delayed nausea and vomiting. In relation to concerns about the use of corticosteroids in non-haematological cancer chemotherapy, we suggest that 8 mg or its equivalent should be used in combination with 5-HT3 antagonists until further research proves otherwise.     

帕洛诺司琼预防成人化疗所致恶心呕吐随机对照试验Meta分析

目的：对帕洛诺司琼预防中国成人恶性肿瘤患者化疗所致的恶心呕吐的疗效和不良反应进行Meta分析。方法：计算机检索Cochrane图书馆、PubMed、EMbase、VIP、CNKI和CBM等电子数据库,查找应用帕洛诺司琼与第1代5-HT3受体拮抗剂预防中国成人化疗所致恶心呕吐的随机对照试验（randomizedcontrolledtrial,RCT）。对符合条件的RCT,进行质量评价和资料提取,采用RevMan5．2软件进行Meta分析,并采用推荐分级的评价、制定与评估（gradesofrecommendationsassessment,developmentandevaluation,GRADE）系统对证据质量和等级推荐进行分级。结果：共纳入10个RCT,共计接受中高度致吐性化疗患者1774例。Meta分析显示,与第1代5-HT3受体拮抗剂比较,帕洛诺司琼预防急性化疗所致恶性呕吐有效率（RR=1．08,95％CI：1．02～1．15,P=0．02）、迟发性化疗所致恶性呕吐有效率（RR=1．34,95％CI：1．21～1．48,P〈0．001）和全程化疗所致恶性呕吐有效率（RR=1．23,95％CI：1．09～1．40,P=0．001）均具有明显优势,且主要不良反应头痛（RR=0．91,95％CI：0．55～1．52,P=0．72）和便秘（RR=1．00,95％CI：0．66～1．53,P=0．99）差异无统计学意义。GRADE系统评价结果显示,证据级别均为低级别,推荐等级为弱推荐。结论：帕洛诺司琼预防成人化疗所致恶心呕吐安全、有效;帕洛诺司琼可优先考虑用于预防中高度致吐性化疗方案的恶心呕吐。     

三种5-HT_3受体拮抗剂预防mFOLFOX6化疗所致恶心呕吐的成本-效果比较

目的探讨3种5-HT3受体拮抗剂预防m FOLFOX6化疗所致恶心呕吐的经济学效益。方法选取2015年9月至2016年12月间海门市人民医院收治的120例接受m FOLFOX6化疗的患者,采用随机数字表法分为昂丹司琼(A)组、阿扎司琼(B)组和帕洛诺司琼(C)组,每组40例。分别采用昂丹司琼、阿扎司琼和帕洛诺司琼对恶心呕吐进行防治,比较3组患者的临床有效率,采用药物经济学成本-效果分析法进行评价比较。结果 A组有效率为65.0%,成本为179.79元,成本效果比(C/E)为2.77;B组有效率为90.0%,成本为306.00元,C/E为3.40;C组有效率为92.5%,成本为384.70元,C/E为4.16。结论阿扎司琼对于防治m FOLFOX6化疗所致的恶心呕吐最经济有效。     

Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists

Purpose

The ferret cisplatin emesis model has been used for ~30?years and enabled identification of clinically used anti-emetics. We provide an objective assessment of this model including efficacy of 5-HT₃ receptor antagonists to assess its translational validity.

Methods

A systematic review identified available evidence and was used to perform meta-analyses.

Results

Of 182 potentially relevant publications, 115 reported cisplatin-induced emesis in ferrets and 68 were included in the analysis. The majority (n?=?53) used a 10?mg?kg^?1 dose to induce acute emesis, which peaked after 2?h. More recent studies (n?=?11) also used 5?mg?kg^?1, which induced a biphasic response peaking at 12?h and 48?h. Overall, 5-HT₃ receptor antagonists reduced cisplatin (5?mg?kg^?1) emesis by 68% (45?C91%) during the acute phase (day 1) and by 67% (48?C86%) and 53% (38?C68%, all P?<?0.001), during the delayed phase (days 2, 3). In an analysis focused on the acute phase, the efficacy of ondansetron was dependent on the dosage and observation period but not on the dose of cisplatin.

Conclusion

Our analysis enabled novel findings to be extracted from the literature including factors which may impact on the applicability of preclinical results to humans. It reveals that the efficacy of ondansetron is similar against low and high doses of cisplatin. Additionally, we showed that 5-HT₃ receptor antagonists have a similar efficacy during acute and delayed emesis, which provides a novel insight into the pharmacology of delayed emesis in the ferret.     

5-HT3受体拮抗剂联合地塞米松预防化疗所致恶心呕吐的临床疗效

目的 探讨第一代5-羟色胺3受体拮抗剂（5-HT3RA）托烷司琼（Tropisetron,TRO）与第二代5-HT3RA帕洛诺司琼（Palonosetron,PAL）联合地塞米松预防化疗所致恶心和呕吐的疗效及安全性。 方法 选择2015年1月至2018年12月在广西医科大学附属肿瘤医院诊治,并接受含有高度催吐风险方案进行多日化疗的192例肿瘤患者为研究对象。采用随机、交叉自身对照法分为PAL组和TRO组,其中PAL组止吐方案为帕洛诺司琼联合地塞米松,TRO组为托烷司琼联合地塞米松方案。比较两组患者恶心、呕吐发生率及止吐药物相关不良反应发生率。结果 PAL组和TRO组患者在急性期（d1）的恶心和呕吐发生率差异均无统计学意义（均P>0.05）,PAL组在延迟期（d2~5）及全程（d1~5）的恶心发生率均低于TRO组（均P<0.05）,在延迟期（d3~d4）及全程呕吐的发生率亦低于TRO组（均P＜0.05）。TRO组有57.3%的患者需重复使用5-HT3RA,高于PAL组的39.3%（P＜0.05）。与止吐药物相关或可能相关的不良反应包括便秘、腹胀、头痛和呃逆等,两组不良反应发生率差异无统计学意义（P>0.05）。 结论 第二代5-HT3RA帕洛诺司琼防治延迟性化疗所致恶心和呕吐的疗效优于第一代5-HT3RA托烷司琼,安全性良好。     

Prevention of nausea and vomiting in cisplatin-treated patients by a selective 5-hydroxytryptamine (5-HT3) receptor antagonist, ICS 205-930

The results of an open study designed to evaluate the prevention of cisplatin-induced emesis by the specific 5-HT3 receptor antagonist ICS 205-930 are reported. Fifty-four cancer patients, treated with diverse chemotherapy regimens, all including cisplatin (greater than = 50 mg/m2), received ICS 205-930 for a total of 165 courses. ICS 205-930 (10 mg) was given i.v. immediately before the cisplatin infusion and a second 10-mg dose was given immediately after. In 109 courses (66%) the patients did not have any vomiting episodes. Nausea was absent in 44.8% of courses. More than 3 vomiting episodes occurred only in 17 (10.4%) courses, and severe nausea only in 11 (6.6%). ICS 205-930 was extremely well tolerated. Mild headache occurred during 7 courses (4.2%) in 4 patients, hypotension during 5 courses (3%) in 3 patients and lipothymia in 2 courses (1.2%) in 2 patients. These results suggest that ICS 205-930 is an effective and well tolerated antiemetic drug in patients receiving cisplatin chemotherapy.     

Hypnosis for nausea and vomiting in cancer chemotherapy: a systematic review of the research evidence

To systematically review the research evidence on the effectiveness of hypnosis for cancer chemotherapy-induced nausea and vomiting (CINV). A comprehensive search of major biomedical databases including MEDLINE, EMBASE, ClNAHL, PsycINFO and the Cochrane Library was conducted. Specialist complementary and alternative medicine databases were searched and efforts were made to identify unpublished and ongoing research. Citations were included from the databases' inception to March 2005. Randomized controlled trials (RCTs) were appraised and meta-analysis undertaken. Clinical commentaries were obtained. Six RCTs evaluating the effectiveness of hypnosis in CINV were found. In five of these studies the participants were children. Studies report positive results including statistically significant reductions in anticipatory and CINV. Meta-analysis revealed a large effect size of hypnotic treatment when compared with treatment as usual, and the effect was at least as large as that of cognitive-behavioural therapy. Meta-analysis has demonstrated that hypnosis could be a clinically valuable intervention for anticipatory and CINV in children with cancer. Further research into the effectiveness, acceptance and feasibility of hypnosis in CINV, particularly in adults, is suggested. Future studies should assess suggestibility and provide full details of the hypnotic intervention.     

The role of the 5-HT3 antagonists ondansetron and dolasetron in the control of delayed onset nausea and vomiting in patients receiving moderately emetogenic chemotherapy

Background: 5-HT₃ antagonists are effective inreducing the acute nausea and vomiting caused by cancer chemotherapy. However,it is not clear whether continuing these agents beyond twenty four hours isuseful in controlling emesis on days two to seven after chemotherapy.Patients and methods: Four hundred seven patients receivingmoderately emetogenic chemotherapy who had been given dexamethasone 8 mg i.v.and either ondansetron 32 mg i.v. or dolasetron 2.4 mg/kg i.v. were randomizedto continue either an oral form of their 5-HT₃ antagonist(ondansetron 8 mg b.i.d. or dolasetron 200 mg daily) plus dexamethasone 8 mgp.o. daily or dexamethasone alone for days two to seven. Endpoints assessedby self-report were: 1) complete control (no vomiting, no rescue medications,no missing data) of emesis; 2) nausea severity; and 3) quality-of-life asmeasured by the EORTC QLQ-C30.Results: Continuation of 5-HT₃ antagonists improvedslightly, but not significantly, the complete control rate (47% vs.41%; P = 0.24 one-sided) after chemotherapy. However, mean nauseaseverity was significantly (P = 0.015 one sided) reduced (by 3 mm on a10 cm scale) on the combined arm. Minimal differences in quality of life wereobserved.Conclusion: The benefit of continuing 5-HT₃antagonists beyond 24 hours is modest and the merits of routine use in thesecircumstances debatable.     

Effectiveness of oral 5-HT3 receptor antagonists for emetogenic chemotherapy

PURPOSE/OBJECTIVES: To review the efficacy and safety of the oral 5-hydroxytryptamine3 (5-HT3) receptor antagonists and the use of oral and i.v. antiemetic therapy during and after hospital admission. DATA SOURCES: Articles in medical and nursing literature. DATA SYNTHESIS: Use of oral antiemetics may help patients avoid potential complications associated with i.v. administration and be more convenient. They also are likely to lower staff and materials costs compared to i.v. formulations. Oral granisetron is the only oral antiemetic approved in the United States for use with highly emetogenic chemotherapy regimens. Oral dolasetron and ondansetron are indicated for use with moderately emetogenic chemotherapy. CONCLUSIONS: Oral therapy is preferable to i.v. formulations for most patients. The oral 5-HT3 receptor antagonists approved for chemotherapy-induced nausea and vomiting include dolasetron, granisetron, and ondansetron. Oral granisetron is differentiated for its safety, efficacy, and use in highly and moderately emetogenic chemotherapy. IMPLICATIONS FOR NURSING PRACTICE: Oral antiemetics are preferable to i.v. antiemetics because of decreased total costs and greater convenience for patients who are able to ingest oral medication.     

NK-1受体拮抗剂防治顺铂所致恶心呕吐的研究进展

NK-1抑制剂联合5-HT(羟色胺)抑制剂和地塞米松三联标准止吐方案广泛用于顺铂化疗患者恶心呕吐的防治.近年不同NK-1抑制剂及给药方式,以及与不同5-HT抑制剂及其他止吐药物联合用于顺铂恶心止吐防治进展迅速,现综述如下.