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REVIEW Korean J Obstet Gynecol 2011;54(3):127-131 doi: 10.5468/KJOG.2011.54.3.127 pissn 2233-5188 eissn 2233-5196 PROPHYLACTIC ANTIEMETICS THERAPY AGAINST GYNECOLOGIC CANCER CHEMOTHERAPY Keun Ho Lee, MD 1, Yong Il Kwon, MD 2 1 Department of Obstetrics & Gynecology, Seoul St. Mary s Hospital, The Catholic University of Korea School of Medicine; 2 Department of Obstetrics & Gynecology, Hallym University School of Medicine, Seoul, Korea Nausea and vomiting associated with gynecologic cancer chemotherapy are experienced by most of patients receiving chemotherapy. Assessment of vomiting risk by chemotherapy and risk factor are mandatory for rescue of chemotherapy induced nausea and vomiting (CINV). Piled-up evidence based medicine result in prophylactic antiemetics guideline from American Society of Clinical Oncology, Multinational Association for Supportive Care in Cancer, and National Comprehensive Cancer Network. Combination of serotonin receptor antagonist, dexamethason, and with/without NK1 antagonist is the best prophylaxis in patients receiving highly and moderate emetogenic chemotherapy. Other new regimens (palonosetron, transdermal granisetron) are introduced to relieve the active symptom of delayed CINV. Comprehensive understading of pathophysiology of CINV and tailored therapy for the patients are vital in prophylactic antiemetics therapy against gynecologic cancer chemotherapy. Keywords: Nausea, Vomiting, Antiemetics, Guideline 부인암환자에서항암제에의한오심및구토 (chemotherapy induced nausea and vomiting, CINV) 는가장흔하면서다루기힘든부작용이다. 항암제에의한구토는처치후환자가행하는횟수에의해서, 오심은구토를일으킬만한환자의지각증세에의해서측정된다. CINV는항암약물투여환자의약 70-80% 에서경험한다고알려져있고, 특히투여후첫며칠동안에심한증상을보인다고알려져있다 [1]. CINV는 5가지의범주로분류되며, 구토가일어나는시간이항암제투여 24시간이내와이후로나누어서급성 (acute) 과만성 (chronic) 으로나눈다. 예상성혹은선행성 (anticipatory) 구토는다음항암제투여전에나타나는구토를말하며, 돌발성구토는항구토제를사용하더라도나타나는경우이며, 난치성 (refractory) 은항구토제에전혀반응하지않는상태이다. CINV에대한처치법은 1960년대 dexamethasone 등의스테로이드제재를투여하면서시작되었고, 고용량의 metoclopramide를이용하기도하였으며, 이후혼합하여사용하기시작하였다. 1980년대이후나온여러가지 serotonin receptor antagonist계약물로인하여많은임상연구가진행되었고, 이를기초로 1990년대이후부터근거중심에따라서항구토제를처방하기시작하였다. 1990년대말부터여러기관에서권고안이발표되었고, 수차례개선되어 dexamethasone과 serotonin receptor antagonist 이외에새로운 NK1 receptor antagonist 인 aprepitant나 2세대 setron계인 palonsetron 등을포함한적절한항구토제사용에대한지침을마련해주었다. 하지만아직도임상진료권고안의선택이나근거중심진료를선택하는데있어아직많은문제점이 있다. 이글에서는부인종양환자에게보이는 CINV의기전과현재사용되는항구토제의종류및처치법에대하여알아보고자한다. 오심과구토는위와장에서의독성물질을제거하려는일종의보호기전으로뇌실질, chemoreceptor trigger zone (CTZ), 후두, 위장관에서올라오는미주신경등이뇌수질 (medulla) 에위치한구토중추에자극이되 Received: 2010.10.19. Accepted: 2011. 1.31. Corresponding author: Yong Il Kwon, MD 서울특별시강동구길동 445 번지강동성심병원산부인과 Tel: +82-2-2224-2259 Fax: +82-2-2224-2265 E-mail kbgy@hallym.or.kr * 이내용은 2010 년 9 월 30 일제 13 차산부인과교육강연에서발표되었음. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright 2011. Korean Society of Obstetrics and Gynecology WWW.KJOG.ORG 127

KJOG Vol. 54, No. 3, 2011 Table 1. 구토위험도에따른정맥항암제의분류 (From Hesketh PJ. N Engl J Med 2008;358:2482-94. with permission from New England Journal of Medicine. [3]) Level 1 Level 2 Level 3 Level 4 Minimal risk, <10% Low risk, 10 30% Moderate risk, 31 90% High risk, >91% Bevacizumab Bortezomib Carboplatin Carmustine Bleomycin Cetuximab Cyclophosphamide (=< 1.5 g/m 2 ) Cisplatin Busulfan Cytarabine Cytarabine (>g/m 2 ) Cyclophosphamide Cladribine Docetaxel Danunorubicin (>1.5 g/m 2 ) Fludarabine Ehoposide Doxorubicin Dacarbazine Vinblastine Fluorouracil Epirubicin Mechlorethanmine Vincristine Gemcitabine Idarubicin Streptozocin Vinorelbine Ixabepilone Ifosfamide Lapatinib Irinotecan Methotrexate Oxaliplatin Mitomycin Mitoxantrone Paclitaxel Pemetrexed Temsirolimus Topotecan Trastuzumab 어일어난다. 항암제에의한구토는 CTZ, 위장관, 구토중추에위치한신경전달물질수용체를자극시켜서일어나며, 세로토닌 (serotonin), 도파민 (dopamine), P 물질 (substance P), 히스타민 (histamine), 아세틸콜린 (acetylcholine), 아편제 (opiates) 등이관여되어있다고알려져있다 [2]. 항구토제는이러한신경전달물질을억제하는것으로세로토닌수용체억제제로는 dolasetron (Anzemet), granisetron (Kytril), ondanseteron (Zofran), tropisetron (Navoban), palonosetron (Aloxi), mirtazapine (Remeron) 등이있으며, 도파민억제제로는 domperidone, droperidol, metoclopramide, alizapride, prochlorperazine 등이있으며, NK1 수용체억제제는 aprepitant (Emend), casopitant가있으며, 항히스타민제제로 cyclizine, diphenhydramine, dimenhydrinate, meclozine, promethazine, hydroxyzine이있다. 한편 cannabinoids 계로는 cannabis, dronabinol, balilone가있고, benzodiazepine계로 midazolam, lorazepam 등이사용되기도한다. CINV 위험도는반드시치료적요인과환자의요인을고려하여측정해야만한다. 치료관련요인은고용량의항암요법의사용이나단일혹은복합항암요법의사용도고려해야한다. 환자관련요인으로는여자, 젊은나이, 알콜섭취량이없거나적은경우, 이전에 CINV 병력, 멀미 (motion sickness) 경험, 임신당시오조 (hyperemesis) 병력이있다. 게다가더심한구역증상을격을것이라는환자의선입견역시 CINV의위험요인이될수있다. Table 1은 Hesketh [3] 에의한항암제의구토유발위험도에따른분 류표이며, 이를표준으로사용하고있다. 위험도를측정하는데있어서한가지문제점은위험도단계를상승시키는제안을제공하고있지않다는것이다. 그러나중증도위험 (moderate risk) 이하의약제사용하는일부환자들은권고사항의예방적진토제의치료의사용에도불구하고 CINV를경험한다. 이런환자들은권고안의단계를한단계위로상승시키는것이유용하다. 항암약물투여중인암환자에대한권고안은 1999년 American Society of Clinical Oncology (ASCO) [4] 에서처음나온이래, Multinational Association for Supportive Care in Cancer (MASCC) [5] 에서는매 6개월마다홈페이지에서갱신하고있으며, National Comprehensive Cancer Network (NCCN) [6] 에서는매년예방적항구토제권고안을수정해서발표하고있다. 기관별권고안의차이가조금씩있지만서로공유하고있는항구토제의원칙은다음과같다. 1) CINV의치료목표는구역및구토가발생하였을때만한번치료하지않고, 구역및구토가발생하지않도록예방하는것이다. 2) 중증도위험도항암제 (moderate emetogenic chemotherapy, MEC) 와고위험항암제 (highly emetogenic chemotherapy, HEC) 로치료한경우에는 CINV의발생위험기간은적 128 WWW.KJOG.ORG

Keun Ho Lee, et al. Prophylactic antiemetics therapy against gynecologic cancer chemotherapy 어도 4일이며, 이기간동안에는환자는보호를받아야만한다. 3) 세로토닌억제제의경우경구약제나정맥제재의효과는거의동등한것으로간주되어진다. 4) 진토제의선택은항암제의구토부작용정도, 환자의이전진토제복용경험력및다른환자요인에기초하여선택해야한다. 5) 예방적진토제의사용은 CINV risk가 10 이상일때는반드시사용해야만한다. 현재 CINV 치료권고안은곧진토제투여방침과같으며, 이권고안에서이슈가되는것은 dexamethasone, aprepitant (neurokinin 1 antagonist), 5-HT3 receptor antagonist의사용이다. 모든권고안에서는오직첫번째사이클의항암치료에대한권고사항을제공하고있고, 항암제의잠재적구토부작용에기초한적절한치료에도불구하고 CINV 를경험하는환자에대한연구가필요하다. HEC와 MEC 약제를투여받고있는환자에대한최근 NCCN와 MASCC의진토제치료권고사항은 Table 2에요약되어있다. HEC를받는환자에대한권고사항은 Day 1에 aprepitant, a 5-HT3 receptor antagonist, dexamethasone의사용이다 [7-9]. 현재 MASCC는 5-HT3 receptor antagonist 중수용체결합력이우수하고반감기가긴 palonosetron을추천하고있으나아직명백한증거는부족하다 [7]. 이권고안에서는 HEC를투여받는환자에서 delayed CINV를예방하기위해 Day 2-3에 aprepitant를투여하고 Day 2-4에 dexamethasone을투여하는것을권고하고있다. NCCN 권고안에서는임상의의재량에따라보조적치료로 lorazepam이나, histamine receptor blocker 혹은 a proton-pump inhibitor를권고하고있다. lorazepam은종종불안해하는환자에있어서효과적이다 [10]. MEC를투여받는환자에서두권고안모두급성및지연성 CINV를예방하기위해 5-HT3 receptor antagonist와 dexamethasone의투여를권고하고있다. lorazepam, H2 receptor blocker 또는 proton-pump inhibitor의사용은필요에따라서추가한다 (NCCN 권고안 ). Aprepitant의사용은중등도의 emetic risk를가진항암제 (ie, carboplatin, cisplatin [<50 mg/m 2 ], doxorubicin, epirubicin, ifosfamide, irinotecan, or methotrexate) 를투여받는환자에서선택적으로사용해볼수도있으나, 고가의치료비용때문에제한적으로사용되고있다 (NCCN 권고안 ). 일반적으로 1세대 5-HT3 receptor antagonists는효과의기간과구조적으로다름에도불구하고, 진토효과는동일한것으로생각된다. 2 세대 5-HT3 receptor antagonists인 palonosetron는 5-HT3 수용체에 100배정도반응도가높고, 반감기가약 40시간정도로길어서, 한번의투여로급성 CINV뿐만아니라지연성의 CINV에까지효과가있다 [11-14]. 최근 CINV의예방목적으로 FDA 승인을받은 granisetron 은새로운 transdermal 형태로사용한다. 이 transdermal patch는항암제치료시작전 24-48시간전에상지에부착해야만하고이패치는항암치료시작한후로수일동안안정적이고지속적으로체내용량을유지한다. 이제제는비용이높기는하나조절효과가좋아다른 5-HT3 receptor antagonist 사용으로잦은 CINV로인한재입원, 응급실내원, antienmetics의재투여로인한비용을생각하면비슷할것으로생각된다. 전체적으로 5-HT3 receptor antagonist의효과가비슷함에도불구하고대사특성이나다른요인에따라환자의개개인의효과가다양하기때문에이약제들중한가지이상의처방을고려하는것이중요하다. 2010년 NCCN 권고안에서 low-emetic risk chemotherapy에대한 CINV를예방하기위해 dexamethasone, prochlorperazine, metoclopramide 등의단일 antiemetics가항암제투여당일에추천되며, lorazepam과 H2 receptor blocker나 proton-pump inhibitor와함께사용하여도된다. minimal emetic risk와관련된 chemotherapy를받는환자들을위해, routine prophylaxis는추천되지않는다. 그러나돌발성 CINV를경험할수있으므로주의깊게보아야한다. 여러일에나누어서항암제가투여될때에는가장위험도가높은약물에해당되는항구토제를선택하여야한다. 생각보다많은환자들이권고안에따라항구토제를투여받더라도급성혹은지연성 CINV를경험하고있으므로, 이에대한연구가더필요하다. rescue antiemetics로현재권고되는약제는 Table 3 에나와있다. 치료전략으로는이전사용된것과기전이다른항구 Table 2. NCCN & MASCC 항구토제처치권고안 Emetic risk group Acute Delayed High 5-HT3+DEX+APR DEX+APR Anthracycline+Cyclophosphamide (AC) 5-HT3+DEX+APR APR Moderate 5-HT3 (Palonosetron * )+DEX±APR DEX Low DEX No Minimal No No NCCN, National Comprehensive Cancer Network; MASCC, Multinational Association for Supportive Care in Cancer; 5-HT3, serotonin receptor antagonist; DEX, dexamethasone; APR, aprepitant. * specifi ed palonosetron in MASCC guideline, additional APR in NCCN guideline. WWW.KJOG.ORG 129

KJOG Vol. 54, No. 3, 2011 Table 3. 돌발성 CINV의처치약제 (NCCN guideline) Antipsychotics Haloperidol Olanzapine Benzodiazepine Lorazepam Cannabinoid Dronabinol Nabilone Depamine receptor antagonist Metoclopramide Phenothiazine Prochlorperazine Promethazine Serotonin 5-HT3 antagonist Dolansetron Granisetron Ondanseteron Steroid Dexamethasone CINV, chemotherapy induced nausea and vomiting; NCCN, National Comprehensive Cancer Network; 5-HT3, serotonin receptor antagonist. 토제를선택하는것인데, 그예로 prochlorperazine, metoclopramide, haloperidol 등의 dopamine receptor antagonist나 dronabinol, nabilone 같은 cannabinoid receptor agonist 등이있다. phenothiazine 계의 promethazine는노인환자에서조심하게사용되어야하며, 항정신약물로 olanzapine을사용할수도있다. 항구토제에대한권고안이발표된지아주오래되지않았으므로한계가존재하며, 이는잘못측정된이상반응과사용량을포함하는임상시험디자인에서비롯된다. 또한혼합항암약물투여인경우의임상경험은아직급성 CINV에초점을맞추고있었다. 지연성 CINV를이해하기한 serotonin, substance P 등의신경전달물질의기전연구및복수항암투여일마다 5-HT 3 antagonist가포함되어야하는지에대한연구가부족하다. 그리고현재의권고안들은이전의예방적치료에실패한환자들에게는맞지않는다. Evidence-based care의한계를보다잘극복하기위하여더많은관심과연구가필요할것이다 [15]. 부인암항암화학요법에대한예방적항구토제들은최근에많이개발되어대부분안전하게효과적으로사용할수있다. 그러나환자가경험하는증상은의료진의예상보다더많으며, 이에대한올바른접근과평가가우선적으로따라야한다. CINV 처치권고안은근거중심하에종양의사들에게행위와평가를돕기위한임상적도구이다. 그러므로 CINV를가장효과적으로조절하기위해서는이가이드라인에대한이해가필요하며, 환자증상에대한정확한평가가절실하다. 종양의사로서항암환자를대할때예상되는상황과실질적인환자의상태의차이를줄이는것이진정으로환자들에게도움을줄수있는일이자의무일것이다. References 1. Beger AM, Clark-Snow RA. Adverse effects of treatment. In: Devita VT Jr, Hellman S, Rosenberg SA, editors. Cancer: principles & practice of oncology. 6th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2001. p.2869-80. 2. Hesketh PJ, Van Belle S, Aapro M, Tattersall FD, Naylor RJ, Hargreaves R, et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specifi c receptor antagonists. Eur J Cancer 2003;39:1074-80. 3. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008;358:2482-94. 4. Kris MG, Hesketh PJ, Somerfield MR, Feyer P, Clark-Snow R, Koeller JM, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006;24:2932-47. 5. Multinational Association of Supportive Care in Cancer (MAS- CC). Antiemetic guidelines [Internet]. Hillerød (DK): MASCC; c2011 [cited 2011 Mar 7]. Available from: http://www.mascc. org/media/resource_centers/mascc Guidelines_Update.pdf. 6. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Antiemesis. Version 2 [Internet]. Washington (PA): National Comprehensive Cancer Network; c2011 [cited 2010 Sep 2010]. Available from: http:// www.nccn.org. 7. Grote T, Hajdenberg J, Cartmell A, Ferguson S, Ginkel A, Charu V. Combination therapy for chemotherapy-induced nausea and vomiting in patients receiving moderately emetogenic chemotherapy: palonosetron, dexamethasone, and aprepitant. J Support Oncol 2006;4:403-8. 8. Grunberg SM, Dugan M, Muss H, Wood M, Burdette-Radoux S, Weisberg T, et al. Effectiveness of a single-day three-drug regimen of dexamethasone, palonosetron, and aprepitant for the prevention of acute and delayed nausea and vomiting caused by moderately emetogenic chemotherapy. Support Care Cancer 2009;17:589-94. 9. Herrington JD, Jaskiewicz AD, Song J. Randomized, placebocontrolled, pilot study evaluating aprepitant single dose plus palonosetron and dexamethasone for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. Cancer 2008;112:2080-7. 10. Herrstedt J, Roila F; ESMO Guidelines Working Group. Chemotherapy-induced nausea and vomiting: ESMO clinical recommendations for prophylaxis. Ann Oncol 2008;19 Suppl 130 WWW.KJOG.ORG

Keun Ho Lee, et al. Prophylactic antiemetics therapy against gynecologic cancer chemotherapy 2:ii110-2. 11. Eisenberg P, Figueroa-Vadillo J, Zamora R, Charu V, Hajdenberg J, Cartmell A, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer 2003;98:2473-82. 12. Gralla R, Lichinitser M, Van Der Vegt S, Sleeboom H, Mezger J, Peschel C, 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;14:1570-7. 13. Aapro MS, Grunberg SM, Manikhas GM, Olivares G, Suarez T, Tjulandin SA, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol 2006;17:1441-9. 14. Saito M, Aogi K, Sekine I, Yoshizawa H, Yanagita Y, Sakai H, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet Oncol 2009;10:115-24. 15. Naeim A, Dy SM, Lorenz KA, Sanati H, Walling A, Asch SM. Evidence-based recommendations for cancer nausea and vomiting. J Clin Oncol 2008;26:3903-10. 부인암항암화학요법에대한예방적항구토제처치법 1 가톨릭대학교의과대학산부인과학교실, 2 한림대학교의과대학산부인과학교실 이근호 1, 권용일 2 부인암환자에서항암제에의한오심및구토 (chemotherapy induced nausea and vomiting, CINV) 는대부분에서나타난다. 항암제에의한구토의위험요소를평가하는일은치료에있어서도중요하다할수있다. American Society of Clinical Oncology, Multinational Association for Supportive Care in Cancer와 National Comprehensive Cancer Network 등에서근거중심의학에비추어예방목적의항구토제지침을발표하였다. Serotonin receptor antagonist, dexamethasone 등의약제에필요에따라 NK1 antagonist를추가하는것이항암치료를받는환자에있어가장권장할만한예방법이다. 최근들어 palonosetron, transdermal granisetron 등의제제가소개되어항암치료중나타나는오심, 구토에사용이되고있다. 오심및구토에대한병태생리학적이해를높이는것이부인암환자의항암치료에따른예방적항구토제의사용에중요하다할수있다. 중심단어 : 오심, 구토, 항구토제 WWW.KJOG.ORG 131