化疗相关性呕吐治疗进展 上海肿瘤医院 胡夕春.

Presentation on theme: "化疗相关性呕吐治疗进展 上海肿瘤医院 胡夕春."— Presentation transcript:

1 化疗相关性呕吐治疗进展 上海肿瘤医院 胡夕春

2 细胞毒药物在肿瘤治疗中占据越来越重要的地位
恶性肿瘤治疗目标 提高缓解率 延长DFS 根 治 提高生活质量 延长生存期 细胞毒药物在肿瘤治疗中占据越来越重要的地位

3 CINV Compromises Quality of Daily Life
Mean changes in functional domain scores of health-related quality of life after eight days of chemotherapy Group 1 (no nausea or vomiting) Group 2 (vomiting, no nausea) Group 3 (nausea, no vomiting) Group 4 (nausea and vomiting) 10 5.3 5.3 Quality of Life Improved 4.9 5 1.9b 0.8 0.6f Slide 6 A prospective evaluation of 832 cancer patients undergoing their first cycle of moderately to highly emetogenic chemotherapy has quantified the degree to which CINV compromises health-related quality of life.1 All patients were treated for emesis with a 5-HT3 receptor antagonist, either ondansetron or granisetron, before and during the first day of chemotherapy.1 Most patients also received concomitant dexamethasone prior to chemotherapy. The majority of patients continued to take a 5-HT3 receptor antagonist or dexamethasone, or both, for four to six days after chemotherapy.1 Before and after the initial chemotherapy course, patients kept diaries of nausea and vomiting and recorded the effects of CINV in five functional domains and a global domain on the 30-item European Organization for Research and Cancer core Quality-of-Life Questionnaire.1 Responses were stratified into four groups by the presence or absence of nausea or vomiting.1 Data were available for 685 patients. Group 1 (n=166) reported neither nausea nor vomiting at any time during the study; group 2 (n=30) reported vomiting but not nausea; group 3 (n=157) reported nausea but not vomiting; and Group 4 (n=332) reported both nausea and vomiting. Patients in group 4, who experienced nausea and vomiting despite treatment with a 5-HT3 receptor antagonist and dexamethasone, consistently had the lowest scores in domains of physical functioning, cognitive functioning, social functioning, and global quality of life.1 –0.6 –0.6 –0.5d –1.1c –1.1 –2.6 Mean change in score –5 –3.8a Quality of Life Diminished –5.7 –7.4g –10 –8.7 –8.4 –8.8e –10 –15 –14.2 Physical Emotional Cognitive Social Global –20 Functional domain Group 1: n=166; Group 2: n=30; Group 3: n=157; Group 4: n=332 aGroup 1 vs. Group 4, p=0.007; bGroup 1 vs. Group 4, p=0.0001; cGroup 3 vs. Group 4, p=0.0002; dGroup 3 vs. Group 4, p=0.003; eGroup 1 vs. Group 4, p=0.0001; fGroup 2 vs. Group 4, p=0.0005; gGroup 3 vs. Group 4, p=0.002 Adapted from Osoba D et al Support Care Cancer 1997;5:307–313. Reference 1. Osoba D, Zee B, Warr D et al. Effect of postchemotherapy nausea and vomiting on health-related quality of life. Support Care Cancer 1997;5:307–313.

4 Need for Improved Control of CINV
Most distressing adverse effects of chemotherapy before and during 5-HT3 receptor antagonist era   1 Being sick (vomiting) Feeling sick (nausea) 2 Feeling sick (nausea) Loss of hair 3 Loss of hair Being sick (vomiting) 4 Thought of coming for treatment Constantly tired 5 Duration of treatment at the clinic Need for an injection 6 Need to get a needle Constipation 7 Shortness of breat Thought of coming for treatment 8 Constantly tired Affects family or partner 9 Difficulty sleeping Feeling low, miserable (depression) 10 Affects family or partner Feeling anxious or tense Slide 4 The need for improved control of CINV has not changed appreciably after introduction of the 5-HT3 receptor antagonists. In 1983, before 5‑HT3 receptor antagonists became available, these patients cited vomiting and nausea as the most distressing adverse effects of chemotherapy. In 1996, these symptoms maintained their high ranking despite this new drug class.1,2 The introduction of the 5-HT3 receptor antagonists may nevertheless have created an impression among many health-care professionals that CINV was largely controlled. Perhaps this may help explain why in a recent survey, oncologists and oncology nurses substantially underestimated the incidence of CINV, especially delayed CINV, which occurs after the first day of chemotherapy.3 Underscoring the need for improved control of CINV are its potentially serious consequences. These can include medical complications, especially problems of nutrition and hydration, possible prolonged hospitalization due to delayed emesis, a compromised quality of life, and the decision by patients to halt chemotherapy and follow-up.4 Adapted from de Boer-Dennert M et al Br J Cancer 1997;76(8):1055–1061; Coates A et al Eur J Cancer Clin Oncol 1983;19:203–208. References 1. de Boer-Dennert M, de Wit R, Schmitz PIM et al. Patient perceptions of the side effects of chemotherapy: The influence of 5HT3 antagonists. Br J Cancer 1997;76(8):1055–1061. 2. Coates A, Abraham S, Kaye SB et al. On the receiving end—patient perception of the side effects of cancer chemotherapy. Eur J Cancer Clin Oncol 1983;19:203–208. 3. Grunberg SM, Deuson RR, Mavros P et al. Incidence of chemotherapy-induced nausea and emesis after antiemetics. Perception versus reality. Cancer 2004;100:2261–2268. 4. Berger AM, Clark-Snow RA. Adverse effects of treatment. In: DeVita VT Jr et al, eds. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2004:2515–2523.

5 肿瘤治疗相关呕吐 对病人生活质量和抗肿瘤治疗的影响
轻微 ：不适感 严重 ：脱水、电解质紊乱、营养不良、 胃肠道粘膜撕裂出血 治疗依从性降低 治疗贻误 中止有效治疗

6 肿瘤治疗相关性呕吐 定义: 伴随肿瘤治疗过程中发生的恶心呕吐 CINV 化疗相关性恶心呕吐
Chemotherapy – induced nausea and vomiting RINV 放疗相关性恶心呕吐 Radiation-Induced Nausea and Vomiting

7 CINV分类 急性呕吐 化疗后24h内发生 延迟性呕吐 化疗后>24h or 更长时间
暴发性呕吐 预防处理后发生 难治性呕吐 CINV预防、解救治疗失败

8 CINV相关神经递质 5-羟色胺 组胺 P 物质 内啡肽类 GABA* 乙酰胆碱 多巴胺 Emetic Reflex Slide 5
This slide depicts our current understanding of the neurotransmitters involved in chemotherapy-induced nausea and vomiting (CINV), including the most recently identified emetic neurotransmitter, substance P.1–3 Peripheral neuroreceptors and the chemoreceptor trigger zone (CTZ) are known to contain receptors for serotonin, substance P, dopamine, histamine, and other endogenous neurotransmitters. When these receptors are activated, emesis is induced.1,2 In the past 15 years or so, enormous advances have been made in our understanding of the neurochemical pathways involved in CINV. The advent of selective 5-HT3 receptor antagonists has served as a pharmacologic tool for studying the emetic pathways associated with CINV. The introduction of this class of drugs stimulated considerable clinical research and improved our understanding of CINV.4 Where the original preclinical efficacy trials of 5-HT3 receptor antagonists once involved an observation period of 4 hours,4 today we have a better appreciation of delayed symptoms, which can span several days following chemotherapy. The discovery of substance P was first reported in Some 70 years later, we now understand that this neurotransmitter plays an integral role in relaying noxious sensory information to the brain. As a modulator of nociception, it is involved in several physiologic activities, including the vomiting reflex.5 *Gamma-aminobutyric acid. Diemunsch P, Grélot L Drugs 2000;60:533–546. Grunberg SM, Hesketh PJ N Engl J Med 1993;329:1790–1796. Hornby PJ Am J Physiol Gastrointest Liver Physiol 2001;280:G1055–G1060. References Diemunsch P, Grélot L. Potential of substance P antagonists as antiemetics. Drugs 2000;60:533–546. Grunberg SM, Hesketh PJ. Control of chemotherapy-induced emesis. N Engl J Med 1993;329:1790–1796. Hornby PJ. Receptors and transmission in the brain-gut axis. II. Excitatory amino acid receptors in the brain-gut axis. Am J Physiol Gastrointest Liver Physiol 2001;280:G1055–G1060. Andrews PL, Naylor RJ, Joss RA. Neuropharmacology of emesis and its relevance to anti-emetic therapy. Support Care Cancer 1998;6:197–203. DeVane CL. Substance P: A new era, a new role. Pharmacotherapy 2001;21:1061–1069.

9 呕吐发生的解剖学机制 外周通路： 迷走神经传入纤维 、交感神经节、舌咽神经等
催吐化学感受区(Chemoreceptor triggerzone，CTZ)：位于延髓第四脑室两侧，血脑屏障之外 前庭机制 高级皮层中枢的刺激 呕吐中枢（TC）：位于延髓 网状结构的侧面，直接调节 控制呕吐的发生

10 呕吐相关受体及其体内分布 5HT3受体 —— 迷走神经传入纤维、CTZ、孤束核 神经激肽 (neurokinin, NK) 受体
(P物质作用点位于中枢) 多巴胺受体

11 神经递质与呕吐类型 5HT 急性CINV,RINV P物质 急性、延迟性CINV 炎症因子 延迟性CINV 多巴胺 急性CINV

12 Sensory input Anxiety、fear memory Chemoreceptor Trigger Zone
呕吐发生的病理生理学 Cortex Sensory input Anxiety、fear memory Vestibular System Motion Labyrinth disorders ACh H1 Intracerebral projections 前庭神经核 Vomiting Center Chemoreceptor Trigger Zone Chemotherapy ACh H1 5HT3 D2 5HT3 NK1 迷走神经 Mechanical tretch GI mucosal injury chemotherapy Peripheral Pathways 5HT3 Chemo- receptors Adapted from JAMA 2007;298(10):

13 CINV发生的危险因素 化疗药物致吐性：高致吐性化疗药物 病史： 个人因素 既往化疗时发生过呕吐 电解质紊乱 晕动病病史 焦虑
年龄 < 50岁 无乙醇摄入史 孕期呕吐史 女性 对于化疗相关性呕吐，

14 止吐药物的发展历史 约50% ７0% ４０% 自细胞毒药物使用于临床，恶心呕吐的治疗就引起临床医师的高度重视。上世纪70年代，人们就发现糖皮质激素对恶心呕吐具有一定的疗效，稍后，又发现大剂量的对CINVde 疗效。但是，其对恶心呕吐的有效率不高，仅为50%左右。1987年底一个5-ht及抗剂的出现，具有划时代的意义，恶心呕吐的恶控制率达到了70%，但延迟性呕吐的控制率仍然较低。2003年，第一个专门针对延迟性呕吐的药物问世，同时第二代的5HT jikangji 显示出对急性恶习耨图的根号靠那个之以及对延迟性呕吐的疗效，使得CINVde 治疗进入一个新的时期。

15 止吐药物分类 5-羟色胺拮抗剂 NK1 R拮抗剂 多巴胺拮抗剂 吩噻嗪类(异丙嗪、氯丙嗪等) 苯丁酮类(氟哌啶醇) 甲氧氯普胺
根据药物作用的手提，可以将

16 止吐药物分类 皮质激素 苯二氮卓类(劳拉西泮)：皮质机制 大麻酚类(屈大麻酚,大麻隆) 抗阻胺药：止吐和对抗多巴胺受体拮抗剂的张力障碍作用
草药：姜、薄荷

17 皮质激素的止吐作用机制 不详 中枢：可能通过影响脑内前列腺素的活动、调节血脑屏障、抑制皮质向呕吐中枢发放冲动
外周：通过其抗炎作用抑制肠道释放5-羟色胺或干扰胃肠道5-HT3受体的功能

18 5-HT3RA的作用机制 迷走神经 化疗

19 5-HT3 RA的分类 第一代 第二代 Ondansetron（枢复宁）-1984年开发，1991年批准上市 Tropisetron-欧洲
Granisetron-1988年开发，1991 及1994年分别在英国及美国被批准上市 Dolasetron-1997年批准上市 Ramosetron-日本及东亚地区 第二代 Palonosetron-2003年

20 常用5-HT3R拮抗剂的结构 融合的三环结构 与5HT相似的吲哚环
Rojas C, Anesth Analg,2008;107:469 –478.

21 常用5-HT3R拮抗剂的特点 消除半衰期 与5-HT3R亲和力pKi（-㏒[Ki]） 用法 分类 恩丹西酮 3－4h 8.39
8mg，3次/日 第一代 多拉司琼 7.3h 7.6 10mg/日 托烷司琼 8h / 5mg/日 格拉司琼 9h 8.91 3mg/日 雷莫司琼 6h 0.3mg/日 帕洛诺司琼 40h 10.45 0.25mg 第二代

22 第一代5-HT3RA主要临床研究结果 1995 Granisetron 137 中 72.3* 48.2 71.6* 37.3 1996
时间 药物 n 致吐风险 急性 延迟性 呕吐(%) 恶心(%) 1995 Granisetron 137 中 72.3* 48.2 71.6* 37.3 1996 dolasetron 403 中高 42.2 / 1998 Ondansetron 184 高 58 43 187 51 35 2003 191 52.9 38.7 32 2004 ramosetron 134 54 57 41 31.9 2006 98 49.5 221 38.9 N Engl J Med 1995;332: J Clin Oncol 1996,14: Support Care Cancer,2004,2:58–63 Anti-Cancer Drugs 2006, 17:217–224 Annals of Oncology 2006,17: , Cancer 2003;98:2473–82. *：呕吐有效率

23 第二代5-HT3RA —帕洛诺司琼 化学名：2一[1一氮杂双环(2．2．2)辛一3S一基]一2，3，3aS，4，5，6一六氢一1 H一苯并[de]异喹啉一1一酮盐酸盐 分子式为C19H24N2O·HCL 分子量332.87 属第二代高选择性5-HT3受体拮抗剂

24 III期临床研究: 帕洛诺司琼 vs 恩丹西酮预防 中度致吐性化疗所致恶心呕吐
Study Design: Phase III randomized, multicenter, double-blind, active-controlled, stratified, parallel-arm trial Moderately emetogenic chemotherapy (single dose) Active comparator trial (n = 563) Day 1: Palonosetron 0.25 mg IV Palonosetron 0.75 mg IV Ondansetron 32 mg IV No corticosteroid administered prophylactically Patients were followed for 14 days for evaluation Gralla R et al. Ann Oncol. 2003;14:

25 帕洛诺司琼 vs 恩丹西酮: CINV —Complete Response
Palonosetron 0.25 mg (n=189) Palonosetron 0.75 mg (n=189) Ondansetron 32 mg (n=185) Time (hr) 20 40 60 80 100 Acute: 0-24 (Day 1) Delayed: (Days 2-5) Overall: 0-120 (Days 1-5) Complete Response (% of Patients) * 81.0 73.5 68.6 74.1 64.6 55.1 69.3 58.7 50.3 During the acute, delayed, and overall time intervals, significantly more patients treated with palonosetron 0.25 mg achieved a CR compared with those treated with ondansetron (p<0.025; 97.5% CI of the difference does not include zero). During these time intervals, CR rates were numerically higher, but not statistically different, for palonosetron 0.75 mg compared with ondansetron. 1. Gralla R et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14: *97.5% CIs and 2-sided Fisher’s exact test (significance level = 0.025) indicate a difference between palonosetron and ondansetron. Complete response (CR): no emesis, no rescue medication. Gralla R et al. Ann Oncol. 2003;14:

26 帕洛诺司琼/地塞米松vs格拉司琼/地塞米松 ——日本III期临床研究，帕洛诺司琼0.75mg
Saito M,et al.Lancet Oncol. 2009,10(2):

27 帕洛诺司琼预防肿瘤化疗性恶心呕吐的双盲双模拟、随机、阳性药平行对照的多中心临床试验
试验组=111 帕洛诺司琼0.25mg 1次用药 7天观察 对照组=112 格拉司琼 3mg

28 研究设计 盐酸帕洛诺司琼注射液 /空白模拟剂 5ml 空白模拟剂 3ml/ 盐酸格拉司琼注射液 生理盐水 12ml
解救治疗 空白模拟剂 3ml/ 盐酸格拉司琼注射液 20ml Iv 30秒以上 第7天 化疗前半小时 生理盐水 12ml 解救治疗标准：呕吐发作≥2次/日 解救治疗方法：格拉司琼3mg 地塞米松5mg

29 呕吐控制情况 P=0. 1420 P=0.0282 P=0.0140 急性呕吐 CRR 延迟性呕吐CCR 0-7天呕吐 控制情况
有效性结果：试验药盐酸帕洛诺司琼注射液对强烈化疗引起的急性呕吐（0~24h）完全缓解率(CRR)与对照药盐酸格拉司琼注射液相比差异无显著性(85.59%对比78.57%，P＝0.1420)；但前者对化疗引起的延迟性呕吐(24小时~7天)完全控制率(CCR)明显高于对照组(63.96%对比50.00%，P=0.0282)，化疗后未出现呕吐(0~7天)的受试者比例也明显高于对照组(分别为62.16%和46.43%，P=0.0140)。同时，帕洛诺司琼注射液控制化疗引起的恶心的作用优于格拉司琼(P=0.0198)；化疗后人均呕吐发作次数也明显少于格拉司琼(1.76±4.27次/人与3.08±6.20次/人，P=0.0289)。帕洛诺司琼注射液对化疗后呕吐控制时间明显长于格拉司琼(P=0.0377)。两组需要解救治疗的受试者比例(19.82%和30.36%，P＝0.0891)，以及两组受试者人均解救治疗次数(0.38±0.92次/人和0.54±1.04次/人，P＝0.0907)均以试验组较少，但未达到明显的统计学差异。两组解救治疗的时间及治疗后KPS评分下降程度差异亦无明显的统计学意义。 急性呕吐 CRR 延迟性呕吐CCR 0-7天呕吐 控制情况 2017年3月 29 29

30 呕吐控制时间 呕吐为化疗后小时，而对照组为化疗后0.5小时。两组化疗后呕吐控制时间(小时)中位值分别为168.00±112.00(平均)和 ± (平均)，其差异具有显著性(P=0.0377)，提示试验组呕吐控制时间较长。 最早呕吐时间(h) 平均呕吐控制时间(h) 试验组 3.0 121.78±64.87 对照组 0.5 ±70.55 2017年3月 30

31 两组病人用药后恶心程度的比较 数据集 组别 程度 平均分 P 1 2 3 合计 FAS 受试组 49 35 20 7 111
1 2 3 合计 FAS 受试组 49 35 20 7 111 0.86±0.93 0.0198 对照组 33 37 112 1.14±0.94 PPS 46 34 107 0.89±0.93 0.0474 32 31 6 102 1.13±0.93

32 5-HT3RA的疗效-第一代与第二代比较 急性呕吐 第二代 相当或优于 第一代 延迟性呕吐 第二代 优于 第一代 呕吐全程控制 恶心程度

33 palonosetron vs other 5-HT3RA ： Systematic review and meta-analysis
4 个随机对照双盲研究， 1,298例 帕洛诺司琼对照恩丹西酮、格拉司琼和达拉司琼 帕洛诺司琼组急性期或延迟期恶心均较少 RR=0.75; P = RR= 0.73; P < 帕洛诺司琼组急性期或延迟期呕吐均较少 RR = 0.78; P = RR= 0.75; P < 不良反应无差异 J Clin Oncol 27, 2009 (suppl; abstr e20620)

34 帕洛诺司琼预防CINV随机对照研究 ——两种不同的用法
CDDP 20mg/m2 d1-4，VLB 1.6mg/m2 d1-4, dacarbazine 800mg/m2d1 IL-2 9 MIU/m2/d CIV d1-4，IFN alpha 5 MU/m2/d d1-5. PALO d1,4 (n=15) PALO d1,3,5 (n=15) 恶心/呕吐的发作次数 (7天内) N: 137 /V: 70 N: 85 / V: 44 需要解救治疗的次数（7天内） 100 57 呕吐发作的平均次数（21天） 6.2 3.9 恶心影响进食的患者比例（中重度） 41% 31% 恶心影响睡眠的患者比例（中重度） 20% 13% 恶心影响活动患者比例（中重度） 恶心影响社会交往患者比例（中重度） 32% 21% J Clin Oncol 27, 2009 (suppl; abstr e20008)

35 5-HT3 RA的常见不良反应 Saito M,et al.Lancet Oncol. 2009,10(2):

36 阿瑞吡坦联合帕洛诺司琼对照奥氮平联合帕洛诺司琼预防 CINV
D-1 D-2 D1 D2 D3 D4 安慰剂 PAL 0.25 地米 12mg APR 125mg 地米 4mg bid APR 80mg 奥氮平 5mg 奥氮平 10mg 急性期呕吐CR率： 75%（OLN） vs. 44% （ APR） 延迟性呕吐CR率： 62.5%（OLN） vs. 55.6% （APR） 急性期恶心发生率：62.5%（ OLN） vs. 44.2%( APR） 延迟性恶心发生率：62.5% （OLN ）vs. 66.7% （APR） J Clin Oncol，27:15s, 2009 (suppl; abstr 9633)

37 CINV治疗策略的发展 more Monotherapy
( a 5-HT3 RA) Dual Therapy (plus dexamethasone) Triple Therapy (plus dexamethasone and a NK1 receptor antagonist) more References Cocquyt V, Van Belle S, Reinhardt RR et al. Comparison of L-758,298, a prodrug for the selective neurokinin-1 antagonist, L-754,030, with ondansetron for the prevention of cisplatin-induced emesis. Eur J Cancer 2001;37:835–842. Van Belle S, Lichinitser MR, Navari RM et al. Prevention of cisplatin-induced acute and delayed emesis by the selective neurokinin-1 antagonists, L-758,298 and MK-869. Cancer 2002;94:3032–3041. Navari RM, Reinhardt RR, Gralla RJ et al. Reduction of cisplatin-induced emesis by a selective neurokinin-1–receptor antagonist. N Engl J Med 1999;340:190–195. Campos D, Pereira JR, Reinhardt RR et al. Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone. J Clin Oncol 2001;19:1759–1767. Chawla SP, Grunberg SM, Gralla RJ et al. Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting. Cancer 2003;97:2290–2300.

38 CINV治疗策略的发展 more Monotherapy
( a 5-HT3 RA) Dual Therapy (plus dexamethasone) Triple Therapy (plus dexamethasone and a NK1 receptor antagonist) more Slide 7 The clinical pharmacology of aprepitant was also studied as dual therapy, combined with dexamethasone.1 Reference Van Belle S, Lichinitser MR, Navari RM et al. Prevention of cisplatin-induced acute and delayed emesis by the selective neurokinin-1 antagonists, L-758,298 and MK-869. Cancer 2002;94:3032–3041.

39 CINV治疗策略的发展 more Monotherapy
( a 5-HT3 RA) Dual Therapy (plus dexamethasone) Triple Therapy (plus dexamethasone and NK1 receptor antagonist) more Slide 9 Two different studies looked at aprepitant plus dexamethasone and a 5­HT3 receptor antagonist in triple-therapy combination.1,2 References Navari RM, Reinhardt RR, Gralla RJ et al. Reduction of cisplatin-induced emesis by a selective neurokinin-1–receptor antagonist. N Engl J Med 1999;340:190–195. Campos D, Pereira JR, Reinhardt RR et al. Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone. J Clin Oncol 2001;19:1759–1767.

40 CINV治疗策略的发展 more Monotherapy
( a 5-HT3 RA) Dual Therapy (plus dexamethasone) Triple Therapy (plus dexamethasone and NK1 receptor antagonist) more Slide 11 Finally, a dosing study was conducted to determine the most appropriate dose for aprepitant.1 Reference Chawla SP, Grunberg SM, Gralla RJ et al. Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting. Cancer 2003;97:2290–2300.

41 呕吐控制的原则 目标：预防恶心呕吐的发生 中高度催吐风险化疗药物引起恶心呕吐至少持续4天。需要采取措施使患者度过整个危险期
口服和静脉给予止吐药物疗效相当 放化疗前用药 考虑止吐药的毒性 选择止吐药物应考虑抗肿瘤治疗的催吐性、既往止吐的体验、患者的因素 关键词：预防，全程控制，个体化

42 CINV处理步骤 评估 —化疗方案致吐风险评估 —患者个体因素评估 —病史评估 预防方案选择 解救措施

43 肿瘤病人可能导致呕吐的其他因素 部分或完全性肠梗阻 前庭功能障碍 脑转移 电解质紊乱:高钙血症,高血糖症,低钠血症 尿毒症
其他伴随治疗，如阿片类 化疗药物（如长春新碱）导致胃肌轻瘫 精神生理学的因素，如焦虑

44 化疗药物致吐风险 高度致吐风险：呕吐发生率>90%
Altretamine六甲密胺 Carmustine卡莫司汀 Mechlorethamine氮芥

45 化疗药物致吐风险 中度致吐风险：呕吐发生率30%~ 90%

46 化疗药物致吐风险 低度致吐风险：呕吐发生率＜30%

47 化疗药物致吐风险 轻微致吐风险：呕吐发生率＜10%

48 高度致吐风险化疗的药物预防 第1天 第2天 第3天 第4天 12mg 劳 拉 西 泮 125mg po 115mg iv 80mg po
第1天 第2天 第3天 第4天 125mg po 115mg iv 80mg po 80mg po NK1受体 拮抗剂 5-HT3 R 拮抗剂 8-24/3/100/ 5/0.25mg 地 塞 米 松 12mg 8mg 8mg 8mg 0.5-2mg q4-6h 0.5-2mg q4-6h 0.5-2mg q4-6h 劳 拉 西 泮 0.5-2mg q4-6h

49 中度致吐风险化疗的药物预防 第1天 第2天 第3天 12mg 125mg po 115mg iv 80mg po 80mg po NK1受体
第1天 第2天 第3天 125mg po 115mg iv 80mg po 80mg po NK1受体 拮抗剂 5-HT3 R 拮抗剂 8-24/3/100/ 5/0.25mg 地 塞 米 松 12mg 8mg 8mg 0.5-2mg q4-6h 0.5-2mg q4-6h 0.5-2mg q4-6h 劳 拉 西 泮

50 低度致吐风险化疗的药物预防 地塞米松 12 mg /日或 丙氯拉嗪10 mg q4-6 h或
甲氧氯普胺20-40 mg PO q4-6h/1-2 mg/kg IV q3-4h±苯海拉明25-50 mg q4-6 h ±劳拉西泮0.5-2 mg q4-6 h

51 预期性呕吐的预防

52 化疗相关性呕吐的解救治疗 总原则是给予不同类型止吐药 非口服给药 多种药物联合（作用不同途径） 按时给药 足量补液，及时纠正电解质失衡

53 化疗相关性呕吐的解救治疗 丙氯拉嗪 甲氧氯普胺±苯海拉明 劳拉西泮 5-HT3R 氟哌啶醇 屈大麻酚/大麻隆 奥氮平 异丙嗪

54 谢谢支持