오심/구토-부인암 항암화학요법

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1 Managements of CINV (Chemotherapy Induced Nausea and Vomiting) 삼성서울병원부인암센터부인종양전문간호사김상희

2 Objectives CINV 의분류 CINV 의위험인자구토유발정도에따른항암제의분류 CINV 발생기전항구토제 CINV 치료의표준지침

3 Introduction One of the most distressing side effects of chemotherapy Chemotherapy induced nausea & vomiting(cinv) : 70-80% 10-44% experience anticipatory nausea & vomiting Patients experence more nausea than vomiting

4 Introduction Impaired quality of life Uncontroled vomiting : dehydration, electrolyte imbalances, malnutrition, aspiration pneumonia Decreased patient compliance and consequently increased risk of mortality

5 Patient Perceptions The Most Severe Side Effects of Cancer Chemotheyapy

7 Therapy-Related Emesis Patterns 급성오심 / 구토 (Acute) 항암화학요법약제투여후첫 24시간항암제투여후수분 ~ 수시간후발생, 5~6시간후가가장심함대개 24시간이내증상이호전 지연성오심 / 구토 (Delayed) 항암제투여후 24 시간후발생 대개 48~72 시간후가가장심하며, 6~7 일간지속 주로 cisplatin, carboplatin, cyclophosphamide and doxorubicin 예측성오심 / 구토 (Anticipatory) 항암제투여전에시작되는오심 / 구토 이전항암화학요법을받을때구토가심했던환자에게서나타남

8 Therapy-Related Emesis Patterns 돌발성구토 (breakthrough) 예방적진토제를사용했음에도불구하고발생하는오심 / 구토 불응성오심 / 구토 (Refractory) 이전치료시예방이나구토치료에실패한경우, 다음치료를받을때진토제를예방적으로투여해도구토발생이경우진토제는더이상효과가없음

9 Timing and Treatment of CINV

10 Delayed CINV Incidence of CINV May be experienced by up to 80% of patients 24-72hours after receiving chemotherapy Anticipatory CINV Estimated in 14-63% of patients with a median of 33% Triggered by sights, smells, or sounds and is due to inadequate control of N/V in the past Even with antiemetic prophylaxis emesis and nausea have been reported in up to 50% and 76%

12 Risk factors Individual risk factors Female Young to middle-aged Pain Fatigue High tumor burden, metastases Anxiety Poor performance status History of pregnancy-induced nausea and vomiting

13 Risk factors

14 Risk factors-chemotherapy Influence the severity and risk of CINV Type of chemotherapy Dose Administration schedule : divided dose, continuous infusion 시 vomiting 감소, nausea 증가 : short infusion 시 continuous infusion 보다 nausea & vomiting 증가 Combination chemotherapy : more nausea & vomiting

15 1 Treatment-Related Risk factors

16 Emetogenic potential(nccn, 2017 Ver2) Intravenous agents

17 Emetogenic potential(nccn, 2017 Ver2)

18 Pathophysiology 구토에작용하는신경구조 구토중추 (vomiting center, VC) 미주신경 (vagus nerve) 화학수용체유도부위 (chemoreceptor trigger zone, CTZ) 전정기관 (vestibular apparatus) 대뇌피질 (higher cortical center)

19 Pathophysiology 구토중추 (vomiting center, VC) Medulla 에위치하는신경망 구토의최종경로 여러조직으로부터구토자극과관련된신호를받아구토를유발하는운동기관에자극을전달한다.

20 Pathophysiology 미주신경 (vagus nerve) 항암제, 상복부방사선조사, 장폐색등으로인한구토에서중요한역할 화학적자극수용기 : Enterochromaffin cell 손상 5-HT 방출 5HT3 receptor 에결합 구토자극을직접또는 CTZ 통해 vomiting center 전달 기계적자극수용기 : 복부의과팽만, 폐색, 수축 미주신경, 내장신경자극

21 Pathophysiology 화학수용체유도부위 (chemoreceptor trigger zone, CTZ) 제 4 뇌실근처에있는 U 자모양의혈류가많은조직 BBB밖에있어 CSF, blood 에서화학적자극탐지 (drug, biochemical products, toxins) 탐지 음식물섭취나미각혐오, 위장관계움직임과도관련 항암제치료와관련된오심, 구토의주역할

22 Pathophysiology 전정기관 (vestibular apparatus) 내이에위치 Motion sickness 나내이염으로인한오심, 구토와관련됨 화학요법과관련된오심, 구토에큰영향을주지않음 CDDP 같은이독성을지닌약물이전정기관을자극하여이차적으로오심, 구토를일으킬수있음

23 Pathophysiology 대뇌피질 (higher cortical center) Sensory(smell, sight, pain) 반응 Anticipatory Nausea & Vomiting

24 Pathway of CINV

25 Neurotransmitter receptor in CINV Serotonin, Substance P : 오심구토에관여하는말초와중추신경계의가장중요한신경전달물질

26 Post-cisplatin : differential involvement of neurotransmitters over time

27 Grading (NCI-CTC AE)

28 Management of CINV Prevention 이가장중요 약물적중재 Risk factor 사정 예방적치료 적절한항구토제선택 항암제의 emetogenic potentional 확인 이전항구토제의경험확인 오심 / 구토가예상되는전체기간동안투여

29 Antiemetic Agents

30 Managent of CINV Evolution of Antiemetic Agents High dose metochlopramide(serotonin) Combination regimens 1950s 1970s 1980s 1990s 2000s

31 Nursing consideration : constipation, diarrhea, fatigue, hiccups, weakness

32 Recommended Dosing for the Prevention of Nausea and Vomiting IV : Fosaprepitant 150mg IV Day 1(only) : 5-HT3 of choice1 Day1, dexamethasone12mg PO Day1, 8mgPO Day2, 8mgPO bid Day3~4

33 최소 24 시간전, 상완부바깥쪽적용최대 48 시간전에적용할수있다. 치료종료후, 최소 24 시간경과시에패취를제거, 최대 7 일까지적용 Nursing consideration : Headache, constipation or diarrhea, hypotension, dizziness

34 Dopamine receptor antagonists EPS Sx 으로 5 일이상적용 X Metoclopramide 2T(10mg) tid 5days : metoclopramide(10-30mg po/iv, max: 30mg/day, 0.5mg/kg/day) Prochlorpherazine(compazine), Haloperidol(halodol) Indication : Acute & delayed : Moderately emetogenic chemotherapy Common Side effects : Sedation, hypotension, EPS(extrapyramidal reactions), Diarrhea, dry mouth

35 Corticosteroids : Dexamethasone(8-20mg ), methylprednisolone(40-125mg) Reduce dose when used with aprepitant Indication : Combination with 5HT3 receptor antagonists for acute & delayed emesis(moderately to highly emetogenic) : Alone(moderately emetogenic) Mechanism of action : Unclear 타구토제와병행시효과를상승시켜주는역할 Common Side effects : Dyspepsia, Hiccup, anxiety, insomnia, acne, fluid retension, vagina or anal burning, hyperglycemia

36 Benzodiazepines : Lorazepam(Ativan), Alprazolam(Xanax) Indication : Anticipatory nausea and vomiting : Acute or delayed nausea and vomiting in combination with other agents Mechanism of action : CNS 전반에걸쳐있는 GABA2 receptor 와결합하여불안, 안절부절완화 Common Side effects : Sedation, dry mouth, orthostatic hypotension, dizziness

37 Prevention regimen of CINV(NCCN, )

38 항암제들의구토유발가능성정도 ( 건강보험심사평가원, 2018, 2 월 ) level agent (intravenous chemotherapy) 고위험군 (90% 이상 ) High emetic risk (> 90% frequency of emesis) AC combination defined as either doxorubicin or epirubicin with cyclophosphamide Carboplatin AUC 4 Carmustine > 250mg/ m2 Cisplatin Cyclophosphamide > 1,500mg/ m2 Dacarbazine Mechlorethamine Streptozocin 중등도위험군 (30-90%) Moderate emetic risk (30-90% frequency of emesis) Aldesleukin(IL-2) > million units/ m2 Altretamine Amifostine > 300mg/ m2 Arsenic trioxide Azacitidine Bendamustine Busulfan Carboplatin AUC < 4 Carmustine 250mg/ m2 Clofarabine Cyclophosphamide 1,500 mg/ m2 Cytarabine > 200mg/ m2 Dactinomycin Daunorubicin Doxorubicin Epirubicin Idarubicin Ifosfamide Interferon alfa 10 million IU/m 2 Irinotecan Melphalan Methotrexate 250 1,000 mg/ m2 Oxaliplatin Temozolomide

39 Prevention regimen of CINV Emetic risk category High(>90%) Moderate(30-90%) Antiemetic regimens Serotonin receptor antagonist IV Or Granisetron patch (34.3mg) : D1 Dexamethasone : D1,2,3,4 Aprepitant: D1,2,3 Serotonin receptor antagonist : IV + PO Dexamethasone : D1±D2~ Serotonin receptor antagonist : IV + PO Dexamethasone : D1±D2~ Serotonin receptor antagonist PO : D1 Dexamethasone : D1(±D2,3,4) Aprepitant: D1,2,3 약제 high emetic risk moderate emetic risk ondansetron 5일 2일 granisetron 6정 3정 ramosetron 5일 2일

40 Prevention regimen of CINV Emetic risk category Low(10-30%) Minimal(<10%) Oral chemotherapy : high to moderate Oral chemotherapy : low to minimal Antiemetic regimens Dexamethasone or metoclopramide No routine prophylaxis No routine prophylaxis Serotonin receptor antagonist PO Metoclopramide or Prochlorpherazine

41 Management of CINV Non-pharmacologic measures Behavioral intervention : Self-hypnosis, progressive muscle relaxation, guided imagery, music therapy, cognitive distraction Acupuncture(being studied) Acupressure(acute) Dietary intervention

42 Nursing Diagnosis Altered nutrition, less than body requirements Risk for fluid volume deficit Ineffective coping, individual

43 Case - The patient is a 24-year-old woman - Ovary Germ cell tumor - Chemo regimen : BEP(Bleomycin 15mg D1~D3, - Etoposide 100mg D1~D3 Cisplatin 20mg D1~D5)

45 Case Emend 125mg 80mg 80mg none - The patient is a 56-year-old woman - Epithelial ovary cancer(serous, G3, opt) - Chemo regimen : Paclitaxel(175mg/m2)-Carboplatin(AUC5) Onda, Ramo, none none none - Anti emetic drug? D1 D2 D3 D4 Daexa 12mg 8mg 8mg 8mg Palono..

46 Purpose : Oncology nurses 는 multidisciplinary team 으로서적절한항구토제사용을도울수있다. Methods : 531 명의 US oncology nurse, Web based survrey Results: most familiar guideline, NCCN 73%, ASCO 48% delayed phase(25-125h) only 25% administration, guideline only 17% CINV optimally controlled, 39% poored control, ER

47 Oncology nurses 는 CINV 경험하는환자 care 에서중심이되는역할을하고있으며, 최근의 guideline Delayed symptoms 을잘대처 Evidence based guidelines, current treatment options and future therapy

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<303220C6AFC1FD20BCDBB0E6C8A D E687770> 대한내과학회지 : 제 82 권제 5 호 2012 http://dx.doi.org/10.3904/kjm.2012.82.5.532 특집 (Special Review) - 구역과구토 (nausea and vomiting) 항암치료중구역과구토의처치 건양대학교의과대학내과학교실 송경호 Management of Chemotherapy Induced Nausea and Vomiting