Pharmacological Management of Chemotherapy-induced Nausea & Vomiting (CINV)

Transcription

1 Pharmacological Management of Chemotherapy-induced Nausea & Vomiting (CINV) 財團法人彰化基督教醫院 林逸祥藥師

2 Patient Perceptions of the Most Severe Side Effects of Cancer Chemotherapy Ran k Vomiting Nausea Nausea Nausea Fatigue Fatigue 2. Nausea Fatigue Loss of hair Loss of hair Nausea Nausea/vomiting 3. Loss of hair Loss of hair Vomiting Fatigue Taste change Loss of hair 4. Thought of coming for treatment Effect on family Fatigue Vomiting Fever Taste change 5. Length of time treatment takes Vomiting Having to have an injection Taste change Depression or Irritability Blood counts problem 1. Coates A, et al. Eur J Cancer Clin Oncol. 1983;19: Griffin AM, et al. Ann Oncol. 1996;7: De Boer-Dennert M, et al. Br J Cancer. 1997;76: Lindley C, et al. Cancer Pract. 1999;7: Dawn Hershman Arch Drug Info 2008;1: 台灣癌症基金會 關懷癌友調查計畫

3 調查發現癌症病患經過化療後, 最常見的三種副作用 疲憊 (81%) 噁心嘔吐 (71%) 落髮問題 (60%) 疲憊 嘔心噁吐 落髮是三種常見的化療副作用 台灣癌症基金會 關懷癌友調查計畫

4 化療引起的嘔吐機轉

5 化學治療引起噁心嘔吐之類型及定義 急性噁心嘔吐 (Acute) 使用化學治療藥物後,24 小時內 延遲性噁心嘔吐 (Delayed) 使用化學治療藥物後, 超過 24 小時 可能會持續至 120 小時 (Day 5) 預期性噁心嘔吐 (Anticipatory) 使用化學治療藥物開始前數天至數小時發生 突發性噁心嘔吐 (Breakthrough) 已使用預防性處置, 或止吐藥物, 仍發生

6 急性及延遲性嘔吐作用時間不同 急性嘔吐化放療結束 24 小時內的嘔吐 延遲性嘔吐化放療結束 24 小時後, 長達 2-5 天的嘔吐 Adapted from Tavorath R, Hesketh PJ Drugs 1996;52: Used with permission from Adis International Limited.

7 Risk factors for CINV Female Patient specific History of morning sickness Age <50 years History of low alcohol intake (<1.5 oz/day) History of prior CINV History of nausea/vomiting during pregnancy Chemotherapy specific Emetogenic potential of a chemotherapeutic agent Coadministration with other chemotherapeutic agents Dosage of chemotherapeutic agents Rate of intravenous (I.V.) infusion time Repeated cycles of chemotherapy Preexisting anxiety and nausea 1. J Support Oncol. 2003;1: J Clin Oncol. 1997;15(1): Ann Oncol.2006;17(1): Oncologist. 1999;4:

8 化療藥物致吐性風險分級 單一化學治療藥物致吐風險分為四級 高致吐性 >90% 中致吐性 30%-90% 低致吐性 10%-30% 輕微致吐性 <10% 合併化學治療藥物致吐風險分級其藥物組合中, 致吐風險分級最高者為其整體組合之分級

9 Commonly Used Highly and Moderately Emetogenic Chemotherapy Regimens Cancer Type Breast Lung Head and neck Hodgkin lymphoma Colorectal Ovarian AC, TAC, TC, CMF, TCH Regimen Carbo-Tax, Cis-Tax, cisplatin with vinorelbine, cisplatin with gemcitabine, cisplatin with pemetrexed Cisplatin-based or carboplatin-based regimens ABVD, CHOP with or without rituximab, CVP FOLFOX, FOLFIRI, CapeOX, irinotecan Carbo-Tax, IPcisplatin, cisplatin ABVD doxorubicin + bleomycin + vinblastine + dacarbazine;ac doxorubicin + cyclophosphamide; CapeOX oxaliplatin + capecitabine; Carbo-Tax carboplatin + paclitaxel; CHOP cyclophosphamide + doxorubicin + vincristine + prednisone; Cis-Tax cisplatin + paclitaxel; CMF cyclophosphamide + methotrexate + fluorouracil; CVP cyclophosphamide + vincristine + prednisone; FOLFIRI irinotecan + leucovorin + 5-fluorouracil; FOLFOX oxaliplatin + leucovorin + 5-fluorouracil; IP intraperitoneal; TAC docetaxel + doxorubicin + cyclophosphamide; TC docetaxel + cyclophosphamide; TCH doxorubicin + carboplatin + trastuzumab Clin J Oncol Nurs. 2012;16(3):

10 止吐藥物使用原則 1. 以預防噁心嘔吐為目標 2. 病人開始接受化學治療藥物前即給予止吐藥物, 以達到最大止吐效果 3. 止吐藥物的選擇須考量化學治療藥物致吐風險 病人之前使用止吐藥物的反應 病人個人因子 個別止吐藥物之毒性 4. 口服與靜脈給藥之止吐效果相當 ( 口服可以為第一選擇 ) 5. 止吐藥物的使用期間必須考慮化學治療藥物引起噁心嘔吐作用期間 6. 病人接受高度致吐性化學治療藥物, 考慮其致吐風險至少為 3 天 ; 中度致吐性藥物, 致吐性風險至少為 2 天 ; 於整個風險期間, 必須實施嘔吐預防

11 止吐劑類別 Corticosteroids Dopamine antagonists Serotonin (5-HT3) antagonists NK-1 receptor antagonists Cannabinoids (ex:dronabinol nabilone levonantradol) Others

12 止吐劑的發展 The second generation of 5-HT3 RA, Aloxi Emend inj Emend cap Kytril (1991) Zofran (1993) Navoban (1994) Anzemet (1997) Haldol

13 Histamine (H 1 ) receptors play a role in nausea and vomiting caused by the vestibular system (ie, motion sickness) but not CINV 1 ; no role for histamine (H 2 ) receptors in CINV 2 Dopamine is no longer thought to be a key neurotransmitter responsible for CINV, now that the roles of serotonin and substance P are better understood 2 1. Diemunsch P, Grélot L. Drugs. 2000;60: Berger AM et al. In: Cancer: Principles & Practice of Oncology. Lippincott Williams & Wilkins; 2001:

14 常用現有止吐藥物的作用機轉 藥物分類 Drugs 作用機轉 5HT 3 antagonist NK-1 antagonist Corticosteroid BZD Antihistamines Dopamine & 5HT3 receptor Ondansetron, Granisetron, Tropisetron, Dolasetron Palonosetron Aprepitant(Emend) Dexamethasone Lorazepam, Diazepam Diphehydramine Metoclopramide CTZ & peripheral 5HT 3 CTZ substance-p Prostaglandin Sedative & anxiolytic Vestibular nucleus Dopamine antagonist

15 5-HT 3 受體拮抗劑 所有的 5-HT 3 受體拮抗劑皆可以有效地控制化學治療藥物引起之急性嘔吐 併用 Dexamethasone 可增加含有 5-HT 3 受體拮抗劑的治療藥物組合之止吐效用 靜脈注射 Palonosetron 可以有效地預防中致吐性化學藥物所引起之急性與延遲性嘔吐 每日單次之劑量為佳 等效治療劑量下, 口服與靜脈給藥之止吐療效與安全性相當 副作用 : constipation, diarrhea, dry mouth, and fatigue.

16 5-HT3 RA : chemical structure 第一代 5-HT3 RA 第二代 O C H 3 N O C H 3 N H O N H 2 N H O Tropisetron (Navoban) N N C H 3 N H Granisetron (Kytril) O N N N H S e r o t o n i n O N N O O N O H Palonosetron N C H 3 N H Ondansetron (Zofran) Dolasetron (Anzemet) First generation 5-HT 3 antagonists resemble serotonin; palonosetron is structurally distinct

17 Mechanism of Action Conclusions All 5-HT3 RAs structures resemble serotonin... PALO OND GRAN TROP RAMO Potency (NHI cost 元 ) 0.25mg/vial (1107) 4mg/8mg/vial; 8mg/tab (219/296;225) 1mg/3 mg/vial; 1mg/tab (450/959;259) 5mg/vial; 5mg/tab (425;428) 0.3 mg/vial (525) Half Life (hrs) ~9 Binding Affinity Allosteric binding & Positive Cooperativity Inhibition of Receptor Function YES NO NO NO NO Long Lasting Short Lasting Short Lasting Short Lasting Short Lasting Receptor Internalization YES NO NO NO NO Inhibition of 5-HT3 & NK1 receptor cross-talk YES NO NO NO NO

18 皮質類固醇 (Corticosteroids) 單一藥物適用於低致吐性化學治療藥物所引起之嘔吐 Dexamethasone 併用 5-HT 3 受體拮抗劑與 aprepitant, 對於高度或中度致吐性化學治療藥物所引起之嘔吐效果特別有價值 等效治療劑量下, 皮質類固醇之止吐效果與安全性相當 已含皮質類固醇的化學治療藥物組合, 避免另加入 dexamethasone 作為止吐之用 併用 aprepitant 時, 口服皮質類固醇劑量降為原劑量之 50%, 而靜脈注射劑量則下降為 75%

19 NK-1 receptor antagonist Aprepitant(PO); Fosaprepitant (IV), PO : 125 mg on Day 1 of chemotherapy, then 80 mg daily on days 2 and 3, IV : 150 mg on Day 1 only as an infusion over 20 to 30 minutes initiated approximately 30 minutes before chemotherapy. combined with a regimen of dexamethasone (3 ~ 4 days) and a 5HT3 antagonist(only Day 1) Common adverse effects: hiccups (4.6%), asthenia/fatigue (2.9%), increased ALT (2.8%), constipation (2.2%), headache (2.2%), and anorexia (2.0%)..

20 Precaution (1) Aprepitant, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor. Because fosaprepitant is rapidly converted to aprepitant, neither drug should be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. In clinical trials, EMEND increased the AUC of dexamethasone(cyp3a4 substrate), by 2.2-fold on Days 1 and 5; the dexamethasone dose should be reduced by approximately 50% when coadministered with EMEND.

21 Precaution (2) Aprepitant with warfarin may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle. The efficacy of hormonal contraceptives may be reduced during coadministration with Aprepitant and for 28 days after the last dose of Aprepitant.

22 Dopamine 受體拮抗劑 適用於對 5-HT 3 受體拮抗劑 NK-1 受體拮抗劑 dexamethasone 等止吐藥無法耐受或無療效的病人 Phenothiazine ( 如 :prochlorperazine, thiethylperazine);dopamine antagonist, ( 如 :metoclopramide);butyrophenones ( 如 : haloperidol 和 droperidol) 副作用 : muscle spasms and restlessness.

23 Benzodiazepine Lorazepam 在致吐藥物組合中為輔助性角色, 不建議單獨使用 Lorazepam 可以協助預防與治療預期性嘔吐

24 2009 台灣癌症化學治療引起 之噁心嘔吐處理規範

25 急性嘔吐的預防 藥物致吐性分級 高致吐性併用 anthracycline 與 cyclophophamide 中致吐性 於第一天 (day 1) 使用化學治療藥物前 5-HT 3 受體拮抗劑併用 dexamethasone 與 aprepitant 5-HT 3 受體拮抗劑併用 dexamethasone 低致吐性 輕微致吐性 使用 dexamethasone 無須常規性使用止吐用藥

26 延遲性嘔吐的預防 藥物致吐性分級 使用方法 高致吐性 Corticosteroids ( 於第二至第四天使用 ) 併用 aprepitant ( 於第二至第三天使用 ) 併用 anthracycline 與 cyclophophamide Corticosteroids ( 於第二至第三天使用 ) 併用 aprepitant ( 於第二至第三天使用 ) 中致吐性 低或輕微致吐性 使用 Corticosteroids 或 5-HT 3 受體拮抗劑 ( 於第二至第三天使用 ) 無須常規性使用止吐用藥

27 預期性嘔吐的預防 最佳預防方法為儘力控制病人的急性與延遲性嘔吐 預期性嘔吐應用心理性方式處理 考慮 benzodiazepines 為心理性方式之外加或替代治療

28 突發性嘔吐的治療 -1 突發性嘔吐之治療原則為加上不同作用機轉之止吐藥物 ; 各類止吐藥物對於突發性嘔吐之控制效果差別不大 應考量以固定時間且固定間隔方式給予止吐藥物, 不建議以 PRN 方式處理 以靜脈或直腸給藥較口服給藥適當, 因為病人可能正處在嘔吐狀態 確認病人無脫水現象, 並考量其電解質之平衡

29 突發性嘔吐的治療 -2 於下一次化學治療療程前, 重新評估病人狀況, 且需注意無關於本次化學治療引起突發性嘔吐之因素, 其因素如下 : (1) 腫瘤之腦部轉移 (2) 體內電解質不平衡 (3) 腫瘤之腸胃道 (4) 其他疾病

30 化療不必吐 止吐藥緩解噁心感 台灣癌症基金會