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抗がん薬による悪心(おしん)・嘔吐の予防と対応

著者: 齊藤光江 順天堂大学医学部 乳腺腫瘍学講座

監修: 高野利実 がん研有明病院 乳腺内科

著者校正/監修レビュー済:2019/05/23
患者向け説明資料
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
齊藤光江 : 奨学(奨励)寄付など(エーザイ株式会社)[2021年]
監修:高野利実 : 講演料(第一三共,日本イーライリリー,中外製薬,エーザイ,セルトリオン・ヘルスケア・ジャパン),研究費・助成金など(中外製薬,小野薬品工業,MSD,第一三共,エーザイ)[2021年]

改訂のポイント:
  1. 定期レビューを行い、オランザピンとカルボプラチンの扱いに関する各ガイドラインの改訂を紹介した

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 抗癌薬の副作用で、患者が一番辛いと思うのは、かつて悪心・嘔吐であった。抗癌薬の種類にもよるが、シスプラチンに代表される高度催吐性の抗癌薬は、支持療法を行わないと90%以上の患者で投与後24時間以内(急性期)に嘔吐を引き起こすといわれている。
  1. 嘔吐のメカニズムは、すべてが解明されているわけではないが、まず小腸のクロム親和性細胞からのセロトニン(5-HT3)の放出を皮切りに、迷走神経の求心性の刺激が脳にあるchemo-trigger zoneに伝わり、サブスタンスPなる神経伝達物質も作用してvomiting centerを刺激し、今度は遠心性に迷走神経が嘔吐事象に関わる胃の蠕動、唾液腺、呼吸筋などに作用し、嘔吐に至るとされている。
  1. 胃の内容物が口外に出ることを嘔吐といい、内容物がない以外は同じことが起こる場合を空嘔吐、そこまで至らないが吐きそうな感覚を悪心という。
問診・診察のポイント  
  1. 悪心・嘔吐には患者側のリスク因子があって、年齢が若く、女性であり、アルコールを毎日たしなむ習慣がなく、つわりや乗り物酔いの経験があると吐きやすいといわれている。

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文献 

著者: Rudolph M Navari, Rui Qin, Kathryn J Ruddy, Heshan Liu, Steven F Powell, Madhuri Bajaj, Leah Dietrich, David Biggs, Jacqueline M Lafky, Charles L Loprinzi
雑誌名: N Engl J Med. 2016 Jul 14;375(2):134-42. doi: 10.1056/NEJMoa1515725.
Abstract/Text BACKGROUND: We examined the efficacy of olanzapine for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy.
METHODS: In a randomized, double-blind, phase 3 trial, we compared olanzapine with placebo, in combination with dexamethasone, aprepitant or fosaprepitant, and a 5-hydroxytryptamine type 3-receptor antagonist, in patients with no previous chemotherapy who were receiving cisplatin (≥70 mg per square meter of body-surface area) or cyclophosphamide-doxorubicin. The doses of the three concomitant drugs administered before and after chemotherapy were similar in the two groups. The two groups received either 10 mg of olanzapine orally or matching placebo daily on days 1 through 4. Nausea prevention was the primary end point; a complete response (no emesis and no use of rescue medication) was a secondary end point.
RESULTS: In the analysis, we included 380 patients who could be evaluated (192 assigned to olanzapine, and 188 to placebo). The proportion of patients with no chemotherapy-induced nausea was significantly greater with olanzapine than with placebo in the first 24 hours after chemotherapy (74% vs. 45%, P=0.002), the period from 25 to 120 hours after chemotherapy (42% vs. 25%, P=0.002), and the overall 120-hour period (37% vs. 22%, P=0.002). The complete-response rate was also significantly increased with olanzapine during the three periods: 86% versus 65% (P<0.001), 67% versus 52% (P=0.007), and 64% versus 41% (P<0.001), respectively. Although there were no grade 5 toxic effects, some patients receiving olanzapine had increased sedation (severe in 5%) on day 2.
CONCLUSIONS: Olanzapine, as compared with placebo, significantly improved nausea prevention, as well as the complete-response rate, among previously untreated patients who were receiving highly emetogenic chemotherapy. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT02116530.).

PMID 27410922  N Engl J Med. 2016 Jul 14;375(2):134-42. doi: 10.1056/N・・・
著者: Mitsue Saito, Kenjiro Aogi, Ikuo Sekine, Hirohisa Yoshizawa, Yasuhiro Yanagita, Hiroshi Sakai, Kenichi Inoue, Chiyoe Kitagawa, Takashi Ogura, Shoichi Mitsuhashi
雑誌名: Lancet Oncol. 2009 Feb;10(2):115-24. doi: 10.1016/S1470-2045(08)70313-9. Epub 2009 Jan 8.
Abstract/Text BACKGROUND: Palonosetron is a second-generation 5-hydroxytryptamine 3 (5-HT(3))-receptor antagonist that has shown better efficacy than ondansetron and dolasetron in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately emetogenic chemotherapy, and similar efficacy to ondansetron in preventing CINV in patients receiving highly emetogenic chemotherapy. In this phase III, multicentre, randomised, double-blind, double-dummy, stratified, parallel-group, active-comparator trial, we assessed the efficacy and safety of palonosetron versus granisetron for chemotherapy-induced nausea and vomiting, both of which were administered with dexamethasone in patients receiving highly emetogenic chemotherapy.
METHODS: Between July 5, 2006, and May 31, 2007, 1143 patients with cancer who were receiving highly emetogenic chemotherapy (ie, cisplatin, or an anthracycline and cyclophosphamide combination [AC/EC]) were recruited from 75 institutions in Japan, and randomly assigned to either single-dose palonosetron (0.75 mg), or granisetron (40 microg/kg) 30 min before chemotherapy on day 1, both with dexamethasone (16 mg intravenously) on day 1 followed by additional doses (8 mg intravenously for patients receiving cisplatin or 4 mg orally for patients receiving AC/EC) on days 2 and 3. A non-deterministic minimisation method with a stochastic-biased coin was applied to the randomisation of patients. Covariates known to effect emetic risk, such as sex, age, and type of highly emetogenic chemotherapy, were used as stratification factors of minimisation to ensure balance between the treatment groups. Primary endpoints were the proportion of patients with a complete response (defined as no emetic episodes and no rescue medication) during the acute phase (0-24 h postchemotherapy; non-inferiority comparison with granisetron) and the proportion of patients with a complete response during the delayed phase (24-120 h postchemotherapy; superiority comparison with granisetron). The non-inferiority margin was predefined in the study protocol as a 10% difference between groups in the proportion of patients with complete response. The palonosetron dose of 0.75 mg was chosen on the basis of two dose-determining trials in Japanese patients. All patients who received study treatment and highly emetogenic chemotherapy were included in the efficacy analyses (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00359567.
FINDINGS: 1114 patients were included in the efficacy analyses: 555 patients in the palonosetron group and 559 patients in the granisetron group. 418 of 555 patients (75.3%) in the palonosetron group had complete response during the acute phase compared with 410 of 559 patients (73.3%) in the granisetron group (mean difference 2.9% [95% CI -2.70 to 7.27]). During the delayed phase, 315 of 555 patients (56.8%) had complete response in the palonosetron group compared with 249 of 559 patients (44.5%) in the granisetron group (p<0.0001). The main treatment-related adverse events were constipation (97 of 557 patients [17.4%] in the palonosetron group vs 88 of 562 [15.7%] in the granisetron group) and raised concentrations of serum aminotransferases (aspartate aminotransferase: 24 of 557 [4.3%] vs 34 of 562 [6.0%]; alanine aminotransferase: 16 of 557 [2.9%] vs 33 of 562 [5.9%]); no grade 4 main treatment-related adverse events were reported.
INTERPRETATION: When administered with dexamethasone before highly emetogenic chemotherapy, palonosetron exerts efficacy against chemotherapy-induced nausea and vomiting which is non-inferior to that of granisetron in the acute phase and better than that of granisetron in the delayed phase, with a comparable safety profile for the two treatments.
FUNDING: Taiho Pharmaceutical (Tokyo, Japan).

PMID 19135415  Lancet Oncol. 2009 Feb;10(2):115-24. doi: 10.1016/S1470・・・
著者: David G Warr, Paul J Hesketh, Richard J Gralla, Hyman B Muss, Jørn Herrstedt, Peter D Eisenberg, Harry Raftopoulos, Steven M Grunberg, Munir Gabriel, Anthony Rodgers, Norman Bohidar, George Klinger, Carolyn M Hustad, Kevin J Horgan, Franck Skobieranda
雑誌名: J Clin Oncol. 2005 Apr 20;23(12):2822-30. doi: 10.1200/JCO.2005.09.050.
Abstract/Text PURPOSE: This is the first study in which the NK(1)-receptor antagonist, aprepitant (APR), was evaluated for the prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy.
PATIENTS AND METHODS: Eligible breast cancer patients were naive to emetogenic chemotherapy and treated with cyclophosphamide +/- doxorubicin or epirubicin. Patients were randomly assigned to either an aprepitant regimen (day 1, APR 125 mg, ondansetron (OND) 8 mg, and dexamethasone 12 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, APR 80 qd) [DOSAGE ERROR CORRECTED] or a control regimen (day 1, OND 8 mg and dexamethasone 20 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, OND 8 mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary. The primary efficacy end point was the proportion of patients with complete response, defined as no vomiting and no use of rescue therapy, during 120 hours after initiation of chemotherapy in cycle 1. The secondary end point was the proportion of patients with an average item score higher than 6 of 7 on the Functional Living Index-Emesis questionnaire.
RESULTS: Of 866 patients randomized, 857 patients (99%) were assessable. Overall complete response was greater with the aprepitant regimen than with the control regimen (50.8% v 42.5%; P = .015). More patients in the aprepitant group reported minimal or no impact of CINV on daily life (63.5% v 55.6%; P = .019). Both treatments were generally well tolerated.
CONCLUSION: The aprepitant regimen was more effective than the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide.

PMID 15837996  J Clin Oncol. 2005 Apr 20;23(12):2822-30. doi: 10.1200/・・・

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