2016更新的MASCC/ESMO呕吐共识建议

2016 updated MASCC/ESMO consensus recommendations: prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting 2016更新的MASCC/ESMO共识建议：多日化疗、大剂量化疗的恶心呕吐以及爆发性恶心呕吐的预防

Abstract  摘要山东省肿瘤医院呼吸肿瘤内科张品良

Purpose
目的

This review summarizes the recommendations for the prophylaxis of acute and delayed nausea and vomiting induced by multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting as agreed at the MASCC/ESMO Antiemetic Guidelines update meeting in Copenhagen in June 2015.
本综述总结2015年6月在哥本哈根MASCC/ESMO止吐指南更新会议上通过的协议，由多日化疗、大剂量化疗诱发的急性和延迟性恶心呕吐和爆发性恶心呕吐的预防建议。

Methods
方法

A systematic literature search using PubMed from January 01, 2009 through January 06, 2015 with a restriction to papers in English was conducted.
利用PubMed系统性检索分析了2009年1月1日至2015年1月6日限于的英文文献。

Results
结果

There were three phase III randomized trials in patients undergoing high-dose chemotherapy and stem cell transplant and eight single arm non-randomized clinical studies (single in patients undergoing transplantation and one in patients receiving multiple-day chemotherapy treatment). We used a total of two randomized clinical trials in this guideline update. For patients receiving treatment for breakthrough chemotherapy-induced nausea and vomiting, a phase III randomized trial investigating the use of olanzapine versus metoclopramide in patients receiving highly emetogenic chemotherapy and a second single arm study looking at the effectiveness of olanzapine were identified.
有3项Ⅲ期随机试验的患者接受大剂量化疗和干细胞移植，8项单臂非随机临床研究（1项患者接受移植，1项患者接受多日化疗治疗）。在本指南更新中，我们总共使用了两项随机临床试验。对于接受化疗所致爆发性恶心呕吐治疗的患者，一项Ⅲ期随机试验研究了在接受高致吐化疗的患者中对比使用奥氮平与甲氧氯普胺，第二项单臂研究着眼于确定奥氮平的有效性。

Conclusions
结论

It was concluded that for patients receiving high-dose chemotherapy with stem cell transplant, a combination of a 5-HT3 receptor antagonist with dexamethasone and aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 to 4) is recommended before chemotherapy.
得出的结论是，对于接受大剂量化疗联合干细胞移植的患者，在化疗前推荐5-HT3受体拮抗剂联合地塞米松和阿瑞吡坦（125mg，口服，第1天，80mg，口服，第2-4天）。

For patients undergoing multiple-day chemotherapy-induced nausea and vomiting, a 5-HT3 receptor antagonist, dexamethasone, and aprepitant, are recommended before chemotherapy for the prophylaxis of acute emesis and delayed emesis.
对于接受多日化疗引起的恶心呕吐的患者，在化疗前推荐5-HT3受体拮抗剂、地塞米松和阿瑞吡坦来预防急性呕吐和延迟性呕吐。

For patients experiencing breakthrough nausea and vomiting, the available evidence suggests the use of 10 mg oral olanzapine, daily for 3 days. Mild to moderate sedation in this patient population (especially elderly patients) is a potential problem with this agent.
对于爆发性恶心呕吐的患者，可用的证据建议使用奥氮平10mg口服，每日1次共3天。在该患者群（特别是老年患者）中，轻中度的镇静作用，是该药的一个隐患。

Keywords
关键词

CINV
化疗所致恶心呕吐

Multiple-day chemotherapy.
多日化疗。

High-dose chemotherapy.
大剂量化疗。

Breakthrough nauseas and vomiting.
爆发性恶心呕吐。

NK1 receptor antagonists.
NK1受体拮抗剂。

5-HT3 receptor antagonists
5-HT3受体拮抗剂

Introduction
前言

An international expert committee was convened during the 2015 Multinational Association of Supportive Care in Cancer (MASCC) meeting to develop consensus statements on various issues involving chemotherapy-induced nausea and vomiting (CINV). This paper is an update of the recommendations published after the last MASCC/ESMO conference in 2009 [1] and will describe the deliberations concerning multiday chemotherapy, high-dose chemotherapy, and break-through CINV.
在2015年多国癌症支持治疗学会（MASCC）会议期间召开了一个国际专家委员会，形成的共识声明包括化疗所致恶心呕吐（CINV）的各种问题。发布的该声明是推荐的在上次2009年MASCC/ESMO会议以后的更新，介绍有关多日化疗、大剂量化疗和化疗所致的爆发性恶心呕吐。

Methods
方法

A PubMed systematic literature search was carried out for papers published between January 1, 2009 and January 06, 2015. A number of searches were made for high-dose chemotherapy and stem cell transplantation, multiple-day chemotherapy, and breakthrough nausea and vomiting. The first search consisted of (high-dose chemotherapy or multiple-day chemotherapy or stem cell transplantation) and (emesis or CINV or chemotherapy-induced nausea and vomiting or nausea) and prophylaxis. The keywords included were (high dose chemotherapy or multiple-day chemotherapy) and (emesis or CINV or chemotherapy-induced nausea and vomiting or nausea). A second search was done using the key words: (ondansetron OR granisetron OR dolasetron OR tropisetron, OR palonosetron OR ramosetron OR azasetron or metoclopramide OR domperidone OR metopimazine OR prochlorperazine OR olanzapine OR aprepitant OR fosaprepitant OR netupitant OR rolapitant OR casopitant) and (high dose chemotherapy or multiple-day chemotherapy). A third search was done using the keywords prophylaxis and nausea and vomiting and stem cell transplant. The first search resulted in 52 hits, the second in 25 hits, and the third in 34 hits with a total of 111 references. The search was filtered to clinical trials. A total of 40 references was identified. We used a total of 12 Clinical Trials in this guideline update. There are three phase III randomized trials in patients undergoing high-dose chemotherapy and stem cell transplant and eight single arm non-randomized clinical studies (seven in patients undergoing transplantation and one in patients receiving multiple-day chemotherapy treatment).
对2009年1月1日和2015年1月6日之间发表的论文进行PubMed系统性文献检索。对大剂量化疗和干细胞移植、多日化疗、爆发性恶心呕吐进行了大量检索。第一次检索包括（大剂量化疗或多日化疗或干细胞移植）和（呕吐或化疗导致的恶心呕吐或恶心）以及预防。关键词包括（大剂量化疗或多日化疗）和（呕吐或化疗所致的恶心呕吐或恶心）。使用关键词进行第二次搜索：（昂丹司琼或格拉司琼或多拉司琼或托烷司琼或帕洛诺司琼或雷莫司琼或阿扎司琼或甲氧氯普胺或多潘立酮或美托哌丙嗪或丙氯拉嗪或奥氮平或阿瑞匹坦或福沙吡坦或奈妥吡坦或罗拉吡坦或卡索匹坦）和（大剂量化疗或多日化疗）。第三次搜索是使用关键词预防和恶心呕吐以及干细胞移植。第一次搜索结果匹配52，第二次匹配25，第三次匹配34，共111篇参考文献。筛选检索的临床试验。总共确定了40篇参考文献。在本指南更新中，我们共使用了12项临床试验。有3项Ⅲ期随机试验的患者接受大剂量化疗和干细胞移植，8项单臂非随机临床研究（7项患者接受移植，1项患者接受多日化疗治疗）。

A separate search was conducted to identify studies looking at chemotherapy-induced nausea and vomiting for germ cell tumor patients undergoing treatment with multiple-day cisplatin-based chemotherapy. In this search, three studies were identified (one phase III study and two single arm studies).
为识别接受多日以顺铂为基础的化疗治疗的生殖细胞肿瘤患者着眼于化疗所致恶心呕吐的研究进行了独立搜索。该检索发现了三项研究（1项Ⅲ期研究，两项单臂研究）。

A separate search was conducted for breakthrough nausea and vomiting using the following keywords: (ondansetron OR granisetron OR dolasetron OR tropisetron, OR palonosetron OR ramosetron OR azasetron or metoclopramide OR domperidone OR metopimazine OR prochlorperazine OR olanzapine OR aprepitant OR fosaprepitant OR netupitant OR rolapitant OR casopitant) and breakthrough nausea or breakthrough vomiting. The first search resulted in seven hits. The search was filtered to clinical trials. A total of three references were identified. We used a total of two clinical trials and one systematic review in this guideline up-date. There was a phase III randomized trial investigating the use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy and a single arm looking at the effectiveness of olanzapine for the treatment of breakthrough chemotherapy-induced nausea and vomiting. A recent systematic review was also included.
使用以下关键词单独搜索爆发性恶心呕吐：（昂丹司琼或格拉司琼或多拉司琼或托烷司琼或帕洛诺司琼或雷莫司琼或阿扎司琼或甲氧氯普胺或多潘立酮或美托哌丙嗪或丙氯拉嗪或奥氮平或阿瑞匹坦或福沙吡坦或奈妥吡坦或罗拉吡坦或卡索匹坦）和爆发性恶心或爆发性呕吐。第一次检索匹配7个。筛选检索的临床试验。总共确定了3篇参考文献。在本指南更新中，我们总共使用了两项临床试验和1篇系统性综述。一项Ⅲ期随机试验探讨了在接受高致吐化疗的患者中使用奥氮平对比甲氧氯普胺治疗化疗导致的爆发性恶心呕吐，而一项单臂研究着眼于奥氮平治疗化疗所致爆发性恶心呕吐的有效性。也包括一项最新的系统回顾。

Results 

结果

High-dose chemotherapy
大剂量化疗

The cause of CINV in patients treated with high-dose chemotherapy with stem cell support is multifactorial. Contributing causes include the use of prophylactic antibiotics and narcotic analgesics prescribed for concurrent mucositis management. An additional confounding factor is the use of total-body irradiation. The natural history of CINV in patients undergoing high-dose chemotherapy and stem cell transplantation is unknown. Most patients undergoing high-dose chemotherapy with stem cell support have experienced emesis with prior chemotherapy or irradiation.
在大剂量化疗和干细胞支持治疗的患者中，化疗所致恶心呕吐的原因是多方面的。促成致因包括处方预防性抗生素和麻醉性镇痛药，为处理并发的粘膜炎，其他混杂因素是使用全身照射。在接受大剂量化疗和干细胞移植的患者中，化疗所致恶心呕吐的自然病程尚不清楚。大多数接受大剂量化疗和干细胞支持的患者有化疗或辐射呕吐。

Until recently, only phase II studies of a 5-HT3 receptor antagonist alone or combined with dexamethasone were published in the antiemetic literature for patients undergoing high-dose chemotherapy with stem cell support. Interpretation of phase II studies is problematic due to the multifactorial nature of CINV in this patient population. A cross comparison of phase II trials is challenging due to the various chemotherapy regimens, duration of high-dose chemotherapy, different patient populations, and tumor types included in these studies. These trials are also underpowered with a small number of patients, and clinical end points are different compared to the standard phase III antiemetic trials, making study comparison as well as interpretation very difficult. In recent years, phase III studies have been published regarding the use of modern three-drug antiemetic prophylaxis for patients undergoing high-dose chemotherapy and stem cell support. A double-blind phase III study randomized 181 patients (179 eligible) to ondansetron and dexamethasone with or without aprepitant given on each day of the high-dose preparative regimen. The study showed a significant reduction in emesis without increasing toxicity or use of rescue medication in patients receiving aprepitant. The CR rate was 82 % with the aprepitant arm versus 66 % (p < 0.001). However, there was no effect in the overall visual analog scale (VAS) for nausea. Another study assessing aprepitant, palonosetron, and dexamethasone demonstrated that the combination was safe and efficacious for the prophylaxis of nausea and emesis in patients receiving high-dose BEAM (carmustine, etoposide, cytarabine, melphalan) prior to hematopoietic SCT. In a study, aprepitant did not modify the pharmacokinetics of high-dose melphalan used as conditioning therapy before stem cell transplantation in patients with multiple myeloma.
直到最近才仅发布了一项接受大剂量化疗加干细胞支持的患者5-HT3受体拮抗剂单独或联合地塞米松止吐的Ⅱ期研究文献。由于在该患者群中化疗所致恶心呕吐的多种因素特征，Ⅱ期研究的解释是有疑问。由于这些研究包括的化疗方案、大剂量化疗的持续时间各种各样、患者群和肿瘤类型不同，因此，Ⅱ期试验的交叉对照是有挑战性的。与标准的Ⅲ期止吐试验相比，这些试验患者数量少且临床终点不同，也存在效力不足，使研究之间的比较和解释非常困难。近年来，已经发表了若干关于在接受大剂量化疗和干细胞支持的患者中使用现代的三药止吐预防的Ⅲ期研究。一项双盲Ⅲ期研究将181例（179例合格）患者随机分入恩丹西酮加地塞米松±大剂量预处理方案时每天1次阿瑞匹坦。研究表明，在接受阿瑞匹坦的患者中，呕吐明显降低且不增加毒性或使用挽救药物。完全缓解率阿瑞吡坦组为82%对66%（p＜0.001）。然而，对总的恶心视觉模拟量表（VAS）没有作用。另外一项评估阿瑞匹坦、帕洛诺司琼和地塞米松在造血干细胞移植前接受大剂量BEAM（卡莫司汀、依托泊苷、阿糖胞苷、马法兰）的患者中预防恶心呕吐的研究表明，联合是安全有效的。在一项研究中，阿瑞匹坦未影响大剂量马法兰作为多发性骨髓瘤患者干细胞移植前条件反射疗法的药代动力学。

The efficacy of aprepitant in patients with multiple myeloma undergoing high-dose chemotherapy with autologous stem cell transplant was investigated in phase II and phase III clinical studies. In the phase III study, patients with multiple myeloma were randomized to receive either aprepitant administered at a dose of 125 mg orally on day 1 and 80 mg orally on days 2 to 4, granisetron (given at a dose of 2 mg orally on days 1 to 4), and dexamethasone (given at a dose of 4 mg orally on day 1 and 2 mg orally on days 2 to 3) or matching placebo, granisetron at the same dose as in the investigational arm and dexamethasone at a dose of 8 mg orally on day 1 and 4 mg orally on days 2 to 3. The high-dose chemotherapy regimen consisted of melphalan at a dose of 100 mg/m2 administered intravenously on days 1 to 2. The autologous stem cell transplant was performed on day 4. The primary end point was a complete response, defined as no emesis and no rescue therapy within 120 h of melphalan administration. A total of 362 patients were available for the efficacy analysis, with 181 in each treatment arm. The CR rate was significantly higher in the aprepitant arm compared to the control group (58 vs. 41 %; 95 % CI, 1.23 to 3.00; p = .0042). Absence of major nausea (94 vs. 88 %; 95 % CI, 1.09 to 5.15; p = .026) and emesis (78 vs. 65 %; 95 % CI, 1.25 to 3.18; p = .0036) within 120 h was significantly improved by aprepitant. The total mean Functional Living Index-Emesis (FLIE) score (±standard deviation) was 114 ± 18 for aprepitant and 106 ± 26 for placebo (p < .001). Svanberg and Birgegard randomized 96 patients to the 5-HT3 receptor antagonist, tropisetron, and dexamethasone with or without aprepitant for 7 days following HDCT and autologous SCT. Thirty-eight patients in the triple therapy regimen had no vomiting compared to 16 patients in the control group, and this difference was statistically significant (p = 0.001). The authors found no significant differences with regard to nausea or use of antiemetic rescue medication between the two groups. The investigators concluded that the use of aprepitant for 7 days following HDCT and autologous SCT improved control of vomiting in these patients.
在Ⅱ期和Ⅲ期临床研究中对阿瑞匹坦在接受大剂量化疗联合自体造血干细胞移植的多发性骨髓瘤患者中的疗效进行了研究。在Ⅲ期研究中，多发性骨髓瘤患者随机接受阿瑞匹坦125mg口服，第1天，80mg口服，第2-4天，格拉司琼（2mg口服，第1-4天）和地塞米松（4mg口服，第1天，2mg口服，第2-3天），或研究组给予相应的安慰剂，格拉司琼的剂量相同，地塞米松8mg口服，第1天，4mg口服，第2-3天。大剂量化疗方案包括马法兰100 mg/m2，静脉注射，第1-2天。在第4天进行自体干细胞移植。主要终点是完全缓解，定义为无呕吐且在给予马法兰的120小时内无挽救治疗。共有362例患者可进行疗效分析，每一治疗组181例。完全缓解率阿瑞吡坦组显著高于对照组（58对41%；95% CI，1.23-3.00；P = 0.0042）。阿瑞吡坦显著改善120小时内的无严重恶心（94%对88%；95% CI，1.09-5.15；P = 0.026）和呕吐（78%对65%；95% CI，1.25-3.18；P = 0.0036）。总的平均呕吐功能性生活指数（FLIE）评分（±标准差）阿瑞吡坦为114±18，安慰剂为106±26（P<0.001）。svanberg和birgegard将96例患者在大剂量化疗和自体干细胞移植后随机分为5-ht3受体拮抗剂、托烷司琼和地塞米松±阿瑞吡坦7天。与对照组的16例患者相比，三联治疗方案中的38例患者无呕吐，且该差异统计学上有显著意义（p=0.001）。作者发现两组之间恶心或使用止吐药物挽救无显著差异。研究者认为，在大剂量化疗联合自体干细胞移植后，使用阿瑞吡坦7天改善这些患者的呕吐控制。< span="">

In summary, the control of nausea and vomiting with high-dose chemotherapy and stem cell transplantation remains a challenge. However, new phase III data supports the addition of aprepitant to a 5-HT3 receptor antagonist and dexamethasone in the management of these patients.
总之，大剂量化疗联合干细胞移植的恶心呕吐控制仍是一个挑战。不过，新的Ⅲ期数据支持对于这些患者的管理将阿瑞匹坦加入到5-HT3受体拮抗剂和地塞米松中。

CINV for high-dose chemotherapy and stem cell transplantation new guideline 

大剂量化疗联合干细胞移植化疗所致恶心呕吐的新指南

The addition of aprepitant to a 5-HT3 receptor antagonist and dexamethasone in the management of these patients is recommended (see Table 1). 

对于这些患者的管理推荐将阿瑞匹坦加入到5-HT3受体拮抗剂和地塞米松中（见表1）。

Multiple-day chemotherapy 

多日化疗

Multiple-day chemotherapy studies, in the present and the past, have included drugs such as dactinomycin, dacarbazine, and ifosfamide. However, as with prior consensus statements, guidelines are possible only with multiple-day cisplatin in patients with germ cell tumors. Guideline updates that provide no new evidence from previous publications do not require any substantive change. Previous multiple-day chemotherapy studies were incorporated in this review as well as newly published data, including a phase III study.
无论是过去还是现在，多日化疗研究包括的药物如更生霉素、达卡巴嗪和异环磷酰胺。然而，正如以前的共识所述，只有联合多日顺铂治疗生殖细胞肿瘤患者时指南才是合适的。指南更新未从以前发表的论文提供新的证据，不需要任何实质性变化。本综述纳入了以前的多日化疗研究，以及新公布的数据，包括一项Ⅲ期研究。

Ondansetron, the first 5-HT3 receptor antagonist, dramatically improved results preventing CINV induced by multiple-day cisplatin, etoposide, and bleomycin (PEB) for testicular cancer. An older study utilizing prochlorperazine demonstrated that on day 1 of a 5-day course of cisplatin, patients experienced a median of 10 emetic episodes. The most severe CINV is seen on days 3–5 as well as delayed CINV days 6–8. The first phase II study with single-agent ondansetron in 35 patients demonstrated that 77 % had no emesis on day 1, and 51 % had two or fewer episodes during the duration of chemotherapy. Subsequent phase III studies documented the value of adding dexamethasone or metopimazine. Thus, the previous MASCC guidelines stated that patients receiving multiple-day cisplatin should be given a 5-HT3 receptor antagonist plus dexamethasone for acute nausea and vomiting and dexamethasone for delayed nausea and vomiting. The optimal duration of dexamethasone is unknown. Some prefer to use 20 mg on days 1 and 2, no dexamethasone days 3–5, and then 4 mg orally twice daily, days 6–8 (for delayed CINV), whereas others have incorporated dexamethasone for eight consecutive days. Acute and chronic toxicity with dexamethasone includes hiccups, insomnia, hyperglycemia, gastroesophageal reflux disease, agitation, and acne. A greater concern is the potential for late toxicity. Four of 47 patients (9 %) receiving multiple-day cisplatin for metastatic testicular cancer developed avascular necrosis of the hip.
昂丹司琼，第一个5-HT3受体拮抗剂，大大改善了多日顺铂、依托泊苷和博莱霉素（PEB）治疗睾丸癌时预防化疗所致恶心呕吐的结果。一项旧的研究显示，在顺铂的第1-5天使用丙氯拉嗪（奋乃静），患者平均呕吐10次。最严重的恶心呕吐见于第3-5天，以及第6-8天的延迟性恶心呕吐。第一项35例患者单药昂丹司琼的Ⅱ期研究证明，77%第1天无呕吐，51%在化疗期间两次或更少。随后的Ⅲ期研究证明了加地塞米松或美托哌丙嗪的价值。因此，以前的MASCC指南指出，接受多日顺铂的患者应给予5-HT3受体拮抗剂加地塞米松治疗急性恶心呕吐和地塞米松治疗迟发性恶心呕吐。地塞米松的最佳持续时间不清楚。有些人喜欢用20mg，第1-2天，第3–5天不用地塞米松，然后4mg口服，每日两次，第6–8天（用于迟发性恶心呕吐），而另外一些人连续8天联合使用地塞米松。地塞米松的急性和慢性毒性包括呃逆、失眠、高血糖、胃食管反流病、焦虑和痤疮。更担心的是潜在的晚期毒性。接受多日顺铂治疗的47例转移性睾丸癌患者中4例（9%）发生股骨头缺血性坏死。

The optimal 5-HT3 receptor antagonist is also unknown, due to a lack of randomized comparative studies. One option is to use palonosetron 0.25 mg IV on days 1, 3, and 5.
由于缺乏随机对照研究，最佳的5-HT3受体拮抗剂也不得而知。一个选择是使用帕洛诺司琼0.25 mg 静脉注射，第1、3和5天。

Aprepitant is the first neurokinin (NK)1 receptor antagonist to be utilized for CINV. In the Hoosier Oncology Group, a phase III study was conducted with a 5-HT3 receptor antagonist plus dexamethasone plus either aprepitant (125 mg on day 3 and 80 mg days 4–7) or placebo in a randomized, double-blind placebo-controlled study in 69 patients. The CR rate was 42 versus 13 % (p < 0.001) favoring aprepitant. Forty-seven percent had at least one emetic episode with the placebo arm versus 16 % with aprepitant (p < 0.001). Patients served as their own control in this double-blinded cross-over study. Thirty-eight patients preferred the aprepitant cycle and 11 placebo (p < 0.001). The VAS for nausea was better, but not significantly superior with the aprepitant arm. Confirmatory supportive evidence with aprepitant was seen in phase II trials conducted in Australia and Japan.
阿瑞吡坦是第一个可用于化疗所致恶心呕吐的神经激肽（NK）1受体拮抗剂。胡热肿瘤小组的一项随机、双盲、安慰剂对照Ⅲ期研究在69例患者中使用5-HT3受体拮抗剂加地塞米松再加阿瑞吡坦（125mg 第3天，80mg 第4–7天）或安慰剂。完全缓解率为42%对13%（p＜0.001）支持阿瑞匹坦。安慰剂组47%与阿瑞匹坦组16%有至少一次呕吐发作（P＜0.001）。该双盲交叉研究使用患者自身对照。38例患者首选阿瑞吡坦，安慰剂组11例（P＜0.001）。恶心的视觉模拟评分法更好，但阿瑞吡坦组无显著优越性。阿瑞吡坦的验证性支持证据见于澳大利亚和日本的Ⅱ期试验。

Multiple-day cisplatin chemotherapy new guidelines 

多日顺铂化疗新指南

Patients receiving multiple-day cisplatin should receive a 5-HT3 receptor antagonist, dexamethasone, and aprepitant for acute nausea and vomiting and dexamethasone for delayed nausea and vomiting. Some prefer to use aprepitant in both acute and delayed nausea and vomiting (aprepitant days 3–7 during a day 1–5 chemotherapy regimen) (see Table 1).
接受多日顺铂的患者应接受一种5-HT3受体拮抗剂、地塞米松和阿瑞匹坦治疗急性恶心呕吐和地塞米松治疗迟发性恶心呕吐。有些人更喜欢在急性和迟发性恶心呕吐时均使用阿瑞匹坦（在第1-5天方案期间第3-7天使用阿瑞匹坦）（见表1）。

Breakthrough nausea and vomiting 

爆发性恶心呕吐

Drugs used to treat CINV should be administered prior to starting chemotherapy to attempt to prevent or mitigate nausea and emesis. Breakthrough nausea and vomiting is defined as nausea and vomiting during chemotherapy in spite of prophylaxis with guideline-directed antiemetics. Several decades ago, chemotherapy-induced emesis was the major concern for patients, family members, and practitioners. The definition of complete remission, in most older and recent studies, is defined as no emetic episodes and no use of rescue medication. Some studies separately incorporate a VAS with ratings of zero (no nausea) to 100-mm worse possible nausea) in an attempt to assess nausea. Today, nausea, during chemotherapy and for several subsequent days, rather than emesis, is the most prevalent problem. Furthermore, VAS merely provides a qualitative assessment of nausea and fails to take into account the duration of nausea.
用于治疗化疗所致恶心呕吐的药物，应在开始化疗之前给予以试图防止或减轻恶心呕吐。爆发性恶心呕吐的定义是在化疗期间尽管预防性应用了指南指导的止吐药仍出现的恶心呕吐。几十年前，化疗引起的呕吐是患者、家庭成员和医护人员主要的担心。在最老和最新的研究中，完全缓解的定义均为无呕吐发作和未使用挽救药物。一些研究在试图评估恶心方面分别结合视觉模拟评分法0（无恶心）-100mm（更重的恶心）。现在，在化疗期间和之后的几天内，恶心，而非呕吐，是最常见的问题。此外，视觉模拟评分法仅提供恶心的定性评估，未能考虑到恶心的持续时间。

Clinicians should be aware that persistent nausea and vomiting might be due to causes other than chemotherapy. CNS metastases, azotemia, hepatic metastases, hypercalcemia, gastrointestinal outlet obstruction, or narcotic analgesics can be confounding factors.
临床医生应该意识到，顽固性恶心呕吐可能是由于化疗以外的原因引起的。中枢神经系统转移、肝转移、氮质血症、高钙血症、胃肠道梗阻或麻醉性镇痛药均可成为干扰因素。

Treatment of breakthrough CINV 

化疗所致爆发性恶心呕吐的治疗

Olanzapine is one of the few agents evaluated in randomized studies. Navari et al. published data on 276 patients treated with highly emetogenic chemotherapy. All patients received prophylaxis with palonosetron 0.25 mg intravenously (IV) plus fosaprepitant 150 mg IV and dexamethasone 12 mg IV day 1 and 8 mg orally days 2–4. Breakthrough nausea and vomiting were observed in 108 evaluable patients who were then randomized to either olanzapine 10 mg orally for 3 days versus a low dose of metoclopramide, 10 mg orally three times daily for 3 days. This reduced dosage has not been demonstrated to be effective. However, the European Medicine Agency mandated this lowered dosage to lessen neurotoxicity. Patients were monitored for 72 h after randomization to assess effectiveness in the treatment of breakthrough CINV. Thirty-nine of 56 (70 %) on olanzapine versus 16 of 52 (31 %) on metoclopramide experienced no further emesis during the 72-h observation period (p < 0.01). Furthermore, 68 % had no nausea with olanzapine compared with 23 % with metoclopramide (p < 0.01). Olanzapine was associated with mild to moderate sedation. Supportive phase II data was published by Chanthawong et al. as well as a systematic review by Hocking et al.
奥氮平是少数随机研究评价的药物之一。Navari等发表的高致吐化疗治疗的276例患者数据。所有患者均接受了预防性应用帕洛诺司琼0.25 mg 静脉注射（IV）加福沙吡坦150 mg IV和地塞米松12mg IV 第1天然后8mg口服 第2-4天。在随机分为奥氮平10mg口服共3天与低剂量的甲氧氯普胺10mg口服每日三次共3天108例可评价的患者中，观察到爆发性恶心呕吐。这个降低后的剂量并未证明有效。不过，欧洲药物管理局强制执行这一较低的剂量以减轻神经毒性。在随机后监测患者72小时以评估爆发性恶心呕吐的治疗效果。在72小时观察期间，56例奥氮平中的39例（70%）对52例甲氧氯普胺中的16例（31%）没有更高程度的呕吐（P＜0.01）。此外，奥氮平68%无恶心，而甲氧氯普胺为23%（P＜0.01）。奥氮平与轻度至中度镇静作用有关。Chanthawong等人发表的Ⅱ期数据以及Hocking等人的系统评价支持。

Breakthrough CINV new guideline 

爆发性恶心呕吐新指南

A different class of antiemetic agent from the agents used for prophylaxis is recommended. The available evidence for breakthrough nausea and vomiting suggests the use of 10 mg oral olanzapine daily for 3 days. The mild to moderate sedation in this patient population, especially elderly patients, is a potential problem with olanzapine (see Table 1).
推荐使用一种与预防使用的药物类型不同的止吐剂。爆发性恶心呕吐的可用证据建议使用奥氮平10mg口服每天一次连续3天。在该患者群中轻至中度的镇静，尤其是老年患者，是奥氮平的一个隐患问题（见表1）。

Conclusions 

结论

Only a few studies have been published on the prophylaxis of acute and delayed nausea and vomiting induced by high-dose chemotherapy, multiple-day chemotherapy, and breakthrough nausea and vomiting since the 2009 consensus conference. Major advances occurred in the last 5 years regarding the management of these patients. Aprepitant is now recommended for the prophylaxis of acute and delayed nausea and vomiting in patients undergoing both high-dose chemotherapy with stem cell transplant and multiple-day chemotherapy. Olanzapine is now incorporated in the treatment of break-through nausea and vomiting. While prophylaxis of vomiting is fairly well managed; nausea remains an unmet medical need. Future studies should concentrate on improving nausea control in these three patient subsets. Randomized trials incorporating olanzapine are indicated looking at nausea as the primary end point.
自2009年共识会议以来，只有少量已发表的有关预防大剂量化疗、多日化疗引起的急性和迟发性恶心呕吐、爆发性恶心和呕吐研究。在过去的5年中，这些患者的管理发生了重大进展。目前推荐阿瑞吡坦用于预防接受大剂量化疗和干细胞移植以及多日化疗患者的急性和迟发性恶心呕吐。目前奥氮平加入到突破恶心呕吐的治疗中。尽管呕吐的预防管理相当不错；但是，恶心仍是一个未满足的医疗需求。将来的研究应集中于改善这三个亚组患者的恶心控制。随机试验表明加入奥氮平需要着眼于恶心作为主要终点。

Table 1 Prevention of nausea and vomiting following multiple-day chemotherapy, high-dose chemotherapy, and breakthrough nausea and vomiting

表1多日化疗、大剂量化疗的恶心呕吐以及爆发性恶心呕吐的预防

Chemotherapy

Recommendations

MASCC level of scientific confidence/level   of consensus

ESMO level of   evidence/grade of recommendation

Old

New

Multiple-day cisplatin   chemotherapy

 Acute

5-HT3 + Dex

5-HT3 + Dex + Apr

Moderate/moderate

II/B

 Delayed

Dex

Dex + Apr

Breakthrough

None

Olanzapine

Moderate/moderate

II/B

High-dose chemotherapy for   stem cell transplant

5-HT3 + Dex

5-HT3 + Dex + Apr

High/high

I/A

化疗

建议

MASCC学术共识等级/共识水平

ESMO证据水平/推荐等级

旧的

新的

多日顺铂化疗

急性

5-HT3   +地塞米松

5-HT3   +地塞米松+阿瑞吡坦

中度/中等的

Ⅱ/B

迟发性

地塞米松

地塞米松 + 阿瑞匹坦

爆发性

无

奥氮平

中度/中等的

Ⅱ/B

造血干细胞移植的大剂量化疗

5-HT3   +地塞米松

5-HT3   +地塞米松+阿瑞吡坦

高/高

I/A

Dex dexamethasone, Apr aprepitant
Dex 地塞米松，Apr 阿瑞吡坦

a Some prefer to use aprepitant in both acute and delayed nausea and vomiting
a有些人更喜欢在急性和迟发性恶心呕吐时均使用阿瑞匹坦

b Mild to moderate sedation especially in elderly patients is a potential problem with olanzapine
b 轻至中度的镇静，尤其是老年患者，是奥氮平的一个隐患问题。