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1 대한내과학회지 : 제 82 권제 5 호 특집 (Special Review) - 구역과구토 (nausea and vomiting) 항암치료중구역과구토의처치 건양대학교의과대학내과학교실 송경호 Management of Chemotherapy Induced Nausea and Vomiting Kyung Ho Song Division of Gastroenterology and Hepatology, Department of Internal Medicine, Konyang University Hospital, Daejeon, Korea Chemotherapy induced nausea and vomiting (CINV) is typically biphasic. The acute phase usually peaks in 5-6 hours after the administration of chemotherapeutic agents and the delayed phase can occur subsequently over 24hours after chemotherapy. Antiemetic therapy is crucial to prevent this unwanted side effect effectively, and NK1 antagonist, 5-HT 3 antagonist, corticosteroid are the main player. The combination and dosing is determined by the emetogenicity of the chemotherapeutic agents to be administrated. (Korean J Med 2012;82: ) Keywords: Antiemetics; Chemotherapy 서론항암화학요법을투여받는다수의환자들이항암제와관련된구역과구토 (chemotherapy-induced nausea and vomiting, CINV) 로힘들어한다. 항암치료스케줄이끝난이후에도식사량이줄거나수행척도 (performance scale), 영양상태의악화로삶의질이저하된다. 때로는항암치료순응도가나빠지는주요원인이된다. CINV 의관리가임상적으로문제가되는주요이유는항암치료를시행하는의사가이의예방에소홀하기때문이다 [1-3]. 항암치료를시행하는내과의사들은 CINV 예방의원칙과팁들을숙지하고적극적인대처를해 야한다. 본고에서는 CINV와관련된여러가이드라인들을고찰하여실제임상적용에도움이되고자한다 [4-6]. 본론항암치료중구역과구토의가능한원인들항암제자체와관련되지않는원인으들로는감염, 전해질이상 ( 고칼슘혈증, 저나트륨혈증 ), 위장관폐쇄, 변비, 암의전이 ( 뇌, 간, 뼈 ), 신생물딸림증후군 (paraneoplastic syndrome), 카켁시아증후군 (cachexia syndrome), 기타약물 ( 마약성진통제, 항생제, 항진균제 ) 이있다 [7]. 이의감별을위해발열, 오 Correspondence to Kyung Ho Song, M.D. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Konyang University Hospital, 158 Gwanjeodong-ro, Seo-gu, Daejeon , Korea Tel: , Fax: , postit@kyuh.ac.kr

2 - Kyung Ho Song. Chemotherapy induced nausea and vomiting - 한, 복부팽만, 복통, 두통, 의미있는체중감소등동반증세와투약력의확인이필요하다. 구토의양상이분출구토라면상부위장관폐쇄, 뇌전이, 요로감염, 고칼슘혈증등의가능성을염두해야한다. CINV 의병태생리와항구토제항암제는대뇌의구토중추 (vomiting center) 를자극할수있는네가지경로중 chemoreceptor trigger zone를통하여구토를유발한다. 이와연관된신경전달물질들은 dopamine, serotonin, substance P, acetylcholine, histamine이며각각 D2, 5-HT 3, NK 1, M1, H1 수용체를통하여작용한다. 그러므로임상에서사용하는항구토약제들은이들수용체의길항제 (antagonist) 들이다. 현재임상에서사용되고있는항구토제는 dopamine antagonist, 5-Hydroxytryptamine type 3 receptor (5HT 3) antagonist, NK 1 antagonist, corticosteroid가주류를이룬다. CINV는특징적으로이상패턴 (biphasic pattern) 을보인다. 즉, 급성구토와지연구토의두악화시점을특징으로한다 [8]. 급성구토는투약수분내지수시간후에발생하며대개 5-6시간째최고조에달하며 24시간이내에소멸된다. 지연구토는투약 24시간이후에발생하며많은항암제들이지연구토를유발할수있다. 지연구토와관련된대표적인항암제로는 cisplatin, carboplatin, cyclophosphamide, doxorubicin 등이있다. 발생형태에따라서는예기성구토 (anticipatory emesis), 돌발성구토 (breakthrough emesis), 불응성구토 (refractory emesis) 로구분한다. 항암치료첫주기부터 CINV의예방이중요한이유는급성구토의발생은지연구토의발생과연관되며 [9], CINV를경험한환자는이어지는주기에서예기성구토를경험할위험성이높아지기때문이다 [8,10]. 급성구토항구토제의효과에따라고치료지수군과저치료지수군으로나눈다. 5-HT 3 antagonist, NK 1 antagonist, corticosteroid는치료지수가높으며 CINV 예방의근간을이룬다. 5-HT 3 antagonist 에는 ondansetron, ganisetron, dolansetron, tropisetron, palonosetron 이있다. 이들은동등한효과와안전성을보인다. 부작용도비슷하여, 경도의두통, 변비, 일시적인무증상의혈청아미노트렌스퍼레이즈상승을유발할수있다. NK 1 antagonist인 aprepitant는중등도의 CYP3A4 (cytochrome P450 3A4) 길항제이며, 때로약물상호작용을고려해야한다. CYP3A4 의대사와관련된약제들은일부항암제들과 clarithromycin, rifampicin, fluconazole과같은항생제항진균제, verapamil, diltiazem과같은칼슘채널길항제, carbamazepine, phenitoin 과같은항경련제, 항구토제로도사용되는 corticosteroid 등이있다 [11]. NK 1 antagonist는 chemoreceptor trigger zone뿐만아니라미주신경에분포하는 NK 1 수용체를길항한다. 항구토목적으로사용되는 corticosteroid는반감기가긴 dexamethasone, methylprednisolone이사용된다. 이둘역시비슷한효능과안전성을보이며작용기전은불분명하다. 저치료지수항구토제로는 metoclopramide, butyrophenone, phenothiazine, cannabinoid 등이있다. 이들은 high emetic risk chemotherapy에는초기조절약제로권고되지않고, 고치료지수군으로도증상이조절되지않을때투약을고려한다. 보조약제로는짧은반감기의벤조다이아제핀계 (lorazepam, alprazolam) 약물과항히스타민제 (diphenhydramine) 를항구토제와병합하여쓰일수있다. 지연구토항암스케줄 24시간이후에발생하는지연구토예방을위해서사용할수있는항구토제는 dexamethasone과 aprepitant Table 1. Emetic risk of intravenous antineoplastic agents [6] Emetic Risk Agent High Carmustine, cisplatin, cyclophosphamide 1,500 mg/m 2, dacarbazine, dactinomycin, mechlorethamine streptozotocin Moderate Azacitidine, alemtuzumab, bendamustine, carboplatin clofarabine, cyclophosphamide < 1,500 mg/m 2, Cytarabine > 1,000 mg/m 2, daunorubicin a, doxorubicin a, epirubicin a, idarubicin a, ifosfamide, irinotecan, oxaliplatin Low Fluorouracil, bortezomib, cabazitaxel, catumaxomab, cytarabine 1,000 mg/m 2, docetaxel, doxorubicin hcl liposome injection, etoposide, gemcitabine, ixabepilone, methotrexate, mitomycin, mitoxantrone, paclitaxel, panitumumab, pemetrexed, temsirolimus, topotecan, trastuzumab Minimal 2-Chlorodeoxyadenosine, bevacizumab, bleomycin, busulfan, cetuximab, fludarabine, pralatrexate, rituximab, vinblastine, vincristine, vinorelbine a These anthracyclines are classified as high emetic risk when combined with cyclophosphamide

3 - 대한내과학회지 : 제 82 권제 5 호통권제 621 호 Table 2. Antiemtic dosing by chemotherapy risk category [5,6] Risk category Dosing on day of chemotherapy Dosing on subsequent days High emetic risk NK 1 antagonist Aprepitant Fosaprepitant 5-HT 3 antagonist Granisetron 125 mg oral 150 mg IV 2 mg oral; 1mg or 0.01 mg/kg IV 80 mg oral; D2-3 Ondansetron 8 mg oral BID; 8 mg or 0.15 mg/kg IV Palonosetron Dolasetron Tropisetron Ramosetron Corticoseroid a Moderate emetic risk b 5-HT 3 antagonist Palonosetron or other 5-HT 3 anatagonists mentioned above Corticoseroid Low emetic risk Corticoseroid or Dopamine receptor antagonist Metoclopramide Minimal emetic risk 0.25 mg IV: 100 mg oral 5 mg oral; 5 mg IV 0.3 mg IV 12 mg oral or IV 0.25 mg IV 8-12 mg oral or IV 8 mg; D2-3 8 mg oral or IV mg oral or IV No routine prophylaxis a If patients do not receive aprepitant, the dose should be adjusted to 20 mg on D1 and 16 mg on D2-4. b If patients receive aprepitant, corticosteroid is only given on D1;12 mg. 8 mg oral or IV; D2-3 or D2-4 이다. 이들약제를 1일째보다는약간작은용량으로항암제투여 2-4일째 (D2-4) 에투약한다 (Tables 1 and 2). CINV 고위험항암제에는두약제모두, CINV 중등도위험항암제에는 dexamethasone 단독을유지한다. CINV 저위험항암제에대해서일상적인지연구토예방은권고되지않는다. 또한경구항암제는지연구토를거의일으키지않으므로, 지연구토예방을위한관례적인항구토제투약은필요없다. 예기구토항암제투약수시간내지수일전부터발생하며구토보다는구역이우세하다. 이전항암치료에대해부정적으로조건화된반응 (conditioned response) 이다. 젊은연령의환자에 서더흔하며발생시젊은연령에서컨트롤이더힘들다. 예기구토를예방하기위해서는첫항암스케줄부터가이드라인에따라강력한항구토약제들을사용할것을권고한다. 예기구토가발생하였을경우에는행동요법 (behavioral therapy) 을시행해볼수있다 [5,6]. 이완, 탈감작, 최면, 음악요법, 침술등의대체의학과 alprazolam, lorazepam의항불안효과를통한조절을사용할수도있다. 돌발성구토예방치료를시행했음에도발생하는구토이며구조요법이필요하다. Prochlorperazine, haloperidol, dronabinol, olanzapine, promethazine 등을병용투여할수있다. 증상이조절되면이

4 - 송경호. 항암치료중구역과구토 - Table 3. Emetic risk by site of radiation therapy Emetic Risk Site of radiation therapy High Total body or total nodal irradiation Moderate Upper abdomen, upper body, half body Low Cranium, craniospinal, head and neck, lower thorax, pelvis Minimal Extremities, breast 들약제를다음스케줄에도투약하며증상이조절되지않는다면다른조합으로투약을시도한다. CINV 관리의실제 NK 1 antagonist, 5HT 3 antagonist, 스테로이드는대개하루 1회투약한다. 단, 지연구토의조절을위해서는스테로이드를하루 2회로증량하여투약할수있다. 일반적으로경구투약을권고하며, palonosetron은주사제만있다. 구역과구토가이미발생하면주사제를사용한다. 5HT 3 antagonist 간의효능차이는없다. CINV 예방을위해투약할땐항구토제를항암제보다 30-60분먼저투약한다. 항구토제의선택과투약기간은항암제의종류와용량에따라달라진다. 여러가이드라인 [4-6] 에서는항구토제없이항암제를투약하였을때의구토발생률에따라구토발생률이 90% 이상일경우 high risk, 30-90% 는 moderate risk, 10-30% 는 low risk, 10% 미만인경우 minimal emetic risk로분류한다 (Table 1). 항암제의구토유발위험도에따른항구토제의투약스케줄은표 2와같다 [5,6]. 항구토제의투약기간은항암제투약시작 분전시작해서지연구토를예방하기위해 high emetic risk의경우 aprepitant와 corticosteroid를 2-4일간, moderate emetic risk의경우 corticosteroid를 2-3일간더유지한다. 여러항암제로이루어진복합항암요법 (combination chemotherapy) 인경우가장높은구토유발위험도를가지는항암제에준해서항구토요법을시행한다. 방사선치료와항암치료의병행시엔항암제와방사선조사부위에따른각각의구토유발위험도를비교하여더높은위험도에따라서항구토제를투약한다. 방사선조사의부위에따른 CINV 위험도구분은표 3에명시하였다 [6]. High to moderate emetic risk 의경우 5-HT 3 antagonist를유지하고 dexamethasone 4mg을첫 5일간유지한다. Low emetic risk의경우 5-HT 3 antagnoist, minimal emetic risk의경우 5-HT 3 antagnoist 또는 dopamine receptor antagonist를사용한다 [6]. 결 항암제치료중구역과구토가발생하였다면항암제자체로인한것인지그외의원인이존재하는지내과의사의판단이필요하다. CINV 는크게급성구토와 24시간이후에발생하는지연구토로나누며이둘을모두예방하기위한항구토제의조합과스케줄이중요하다. 항구토제는 NK 1 antagonist, 5-HT 3 antagonist, corticosteroid가근간을이루며, dopamine receptor antagonist, sedative를병합하여투약할수있다. 항구토제의조합과스케줄은항암제의종류와용량에따라결정된다. 중심단어 : 항구토제 ; 화학요법 론 REFERENCES 1. Fabi A, Barduagni M, Lauro S, et al. Is delayed chemotherapy-induced emesis well managed in oncological clinical practice? an observational study. Support Care Cancer 2003;11: Grunberg SM. Obstacles to the implementation of antiemetic guidelines. J Natl Compr Canc Netw 2009;7: Kaiser R. Antiemetic guidelines: are they being used? Lancet Oncol 2005;6: Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 2010;21(Suppl 5):v232-v National Comprehensive Cancer Network (NCCN). Antiemesis. NCCN Guidelines 2012; Version [cited 2012 April 22]. Available from: physician_gls/pdf/antiemesis.pdf 6. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011;29: Herrstedt J, Roila F; ESMO Guidelines Working Group. Chemotherapy-induced nausea and vomiting: ESMO clinical recommendations for prophylaxis. Ann Oncol 2009;20 (Suppl 4):S156-S Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008;358: Warr DG, Grunberg SM, Gralla RJ, et al. The oral NK(1) antagonist aprepitant for the prevention of acute and delayed chemotherapy-induced nausea and vomiting: pooled data from 2 randomised, double-blind, placebo controlled trials. Eur J Cancer 2005;41:

5 - The Korean Journal of Medicine: Vol. 82, No. 5, Aapro M, Molassiotis A, Dicato M, et al. The effect of guideline-consistent antiemetic therapy on chemotherapyinduced nausea and vomiting (CINV): the Pan European Emesis Registry (PEER). Ann Oncol 2012 Mar 6 [Epub] Hashimoto H, Toide K, Kitamura R, et al. Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control. Eur J Biochem 1993;218:

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PowerPoint Presentation 제 7 회페루자국제암회의 항구토요법지침 (2008 년 3 월최신개정 ) BASED ON: THE CONSENSUS CONFERENCE ON ANTIEMETIC THERAPY* 한국호스피스완화의료학회 * Conference conducted in March 2004 MASCC (Multinational Association of Supportive Care in