병원약사회지 (2013), 제 30 권제 1 호 J. Kor. Soc. Health-Syst. Pharm., Vol. 30, No. 1, 12 ~ 19 (2013) 회원학술보고 Cetuximab 주입관련반응의발생빈도및관련인자분석 서울아산병원약제팀, 이화여자대학교약학대학 a Frequency and Related Factors Analysis of Cetuximab Infusion Reactions Ho-seok Jang, Min-kyoung Kang, Young-seol Heo, Hee-se Kim, Hye-Sun Gwak a, Yeong-cheon Song Department of pharmacy, Asan Medical Center 388-1, Pungnab-dong, Songpa-gu, Seoul, Korea College of Pharmacy, Ewha Womans University 11-1, Daehyun-dong, Seodaemun-gu, Seoul, Korea a Abstract : Monoclonal antibody treatments can result in severe infusion reactions. Among these, cetuximab, mouse-human chimeric monoclonal antibody reported 15~20% infusion reactions (severe infusion reactions 3~5%). However, there are no actual reported incidences in Korea, and little information regarding the prevention, management or outcomes of infusion reactions. This study represents one of the first attempts to describe the clinical consequences regarding the incidence rates of infusion reactions, effect of premedication and test dose. A retrospective chart review was conducted in Asan Medical Center. Eligible patients were treated with cetuximab as either single agents or in combination with additional chemotherapy. Case searches were conducted by electronic medical records from June 2006 to October 2010. Source documents were evaluated for infusion reactions based on the Common Terminology Criteria for Adverse Events version3.0 (CTCAE v3.0). A total of 336 patients (215 men and 121 women) with the mean age of 56 years (27-76 years) were enrolled in this study. 11 patients were identified with infusion reactions. Mild and moderate infusion reactions are 9 ( grade2, 3.3%) and severe infusion reactions are 2 (grade4, 0.6%). In premedication, 7 of 285 patients (2.5%) who received antihistamine were identified with a - 12 -
장호석 : Cetuximab 주입관련반응의발생빈도및관련인자분석 infusion reaction, while 4 of 51 patients (15.2%) who received antihistamine and corticosteroid (p=0.63). 4 of 84 patients (4.8%) treated with monotherapy and 7 of 252 patients (2.8%) treated with combination therapy suffered from infusion reaction (p=0.712). Patients with the administration of test dose (n = 49) experienced infusion reactions were 5 people. Further, 3 of these 5 patients (60%) were identified with infusion reactions at the main dose, not test dose. In addition, 6 patients of the past 2 mg/ml formulation with the unfiltered group (n = 288) (2.1%) and 5 patients of the present 5 mg/ml of the formulation was filtered (n = 48) (10%) were identified with a infusion reactions (p=0.915). It was difficult to find significant factors relating to the infusion reactions because incidences of cetuximab infusion reactions were lower than the previously reported. However, we found that antihistamine with corticosteroids as a premedication tended to reduce infusion reactions and the test dose is not valid. [Key words] Cetuximab, Infusion reaction, Infusion reaction related factor 투고일자 2012. 9. 17; 심사완료일자 2012. 10. 22; 게재확정일자 2012. 11. 9 교신저자강민경 Tel:02-3010-6176 E-mail:mkkang@amc.seoul.kr 최근분자종양학 (molecular oncology) 의발전과더불어종양세포의신호전달체계에대한이해가증가하면서각종암에대한표적치료제들이개발되고있다. 이러한세포표적치료제는항암치료의중요한근간이되고있으며일반적으로세포독성항암제에비해부작용이적어투여시용이할수있다. 그러나, 세포밖에서직접적으로리간드와결합또는리간드결합부위에경쟁적으로결합하여작용을나타내는단클론항체 (monoclonal antibody) 제제의경우일부환자에서주입관련반응이특징적으로나타날수있으며중증발현시치료를중단하게되는원인이되므로치료예후에도지대한영향을미칠수있다. 1) 이러한부작용을감소시키기위해완전한인간항체제제들을개발하고있으나기존의인간 / 마우스키메라형제제의경우는주입관련반응의 빈도가비교적높다고할수있다. Cetuximab(Erbitux ) 은전이성대장암, 전이성편평상피두경부암등에서항암화학요법과병용또는단독요법으로사용되고있으며인간 / 마우스키메라형제제로주입관련반응이높게발생할수있다. 이에대한작용기전이명확하지는않으나 Chung 등에따르면 cetuximab 투여시심각한주입관련반응을경험한대부분의환자에서 galactose-a-1,3- galctose에대한특이적인 immunoglobulin E (IgE) 항체가치료전혈장에서관찰되는것으로보고했다. 2) 따라서, 비IgE 매개반응뿐만아니라 IgE 매개반응으로도주입관련반응이발생할수있으며이를증상에따라구별하는것은어려울수있다. 3) 이러한 cetuximab의주입관련반응발생률은 4, 5) 15~20%, 이중중증반응은최대 3% 에이른다. - 13 -
JKSHP, VOL.30, NO.1 (2013) 이는 taxane계열항암제나 rituximab에비해발생률이낮고, 5, 6) 가벼운오한, 발열, 오심, 발진, 소양감등의증상이대부분이다. 그러나일부환자에서심각한과민반응증상을보이고, 증상발현시적절한처치가이루어지지않을경우환자에게치명적일수있으며영구적으로약을중단하게되는원인이될수 5, 7, 8) 있다. 또한시험용량 (test dose) 을투여하더라도이후반응을정확히예측하기어렵고전처치약물투여시에도주입관련반응을예방하기에는한계가있는것으로알려져있다. 5, 9, 10) 따라서, 이에대한적절한전처치와시험용량투여여부등에대한유효성을평가하고주입관련반응에영향을주는인자들을예측하는것은환자의치료에대한예후뿐만아니라약물사용의경제적인측면에서도중요하다고할수있겠다. 이에본연구에서는단일기관에서의 cetuximab 투여시실제주입관련반응의발생률을알아보고전처치및시험용량투여의적절성및유효성을평가하여주입관련반응과관련된인자들을찾아보고자한다. mg, 1 바이알을 20분간투여후 30분간관찰하여주입관련반응이없을경우나머지용량을투여하였다. 각투여시마다주입관련반응발생여부와중증도를확인하였으며주입관련반응의기준과중증도는 National Cancer Institute의 Common Terminology Criteria for Adverse Events version 3.0(CTCAE v3.0) 을기준으로정의하였다 (Table 1). 11) 이연구를위해다음과같은정보를조사하였다. 1) 기본정보 : 성별, 연령, 체표면적 ( 키, 체중 ), 진단명, 투여 regimen 2) 위험인자분석 : cetuximab 투여횟수, 전처치투여약물종류, 항암제병용여부, 시험용량투여여부, 제형변경여부 3. 통계수집된자료는 SPSS 7.0 프로그램을이용하여분석하였고비모수적분석 (Mann-Whitney U-test) 을이용하여 P-value가 0.05 미만일때통계적유의성이있다고평가하였다. 연구방법 1. 대상환자 2006년 6월부터 2010년 10월까지서울아산병원에서 cetuximab 단독혹은타항암제와병용하여투여받은 336명의환자를대상으로연구를진행하였다. 2. 연구방법후향적, 관찰적, 추적연구로전자의무기록 (electronic medical record, EMR) 을바탕으로환자에대한자료를수집하고분석하였다. Cetuximab 투여는 400 mg/m 2 부하용량투여후매주 250 mg/m 2 을투여하는요법과 500 mg/m 2 을 14일마다투여하는요법으로사용하였다. 시험용량 (test dose) 을투여하는경우, 총투여용량에서 100 연구결과 1. 환자기본정보연구기간내 cetuximab을투여받은환자의평균연령은 58세로연령범위는 25~76세였고성별은남성이 215명 (64%) 으로여성에비해많았다. 암종별로는대장암이 293명 (87.2%) 으로대부분을차지했으며두경부암이 42명 (12.5%) 으로그뒤를이었다. 242명 (75%) 의환자가항암제와같이 cetuximab을투여받았으며병용투여된항암제로는 irinotecan, 5-fluorouracil 등이있었다. Cetuximab 투여시전처치약물로는항히스타민단독투여가 285명 (84.8%) 을차지하였으며원내지침변경으로 2009 년 5월부터투여된 51명의환자는첫투여시 dexamethasone을항히스타민제와병용투여하였다. 시험용량또한기존에는투여하지않았으나 2009-14 -
장호석 : Cetuximab 주입관련반응의발생빈도및관련인자분석 Table 1. 주입관련반응의일반적징후와증상 11) Common signs and symptoms Cytokine release syndrome/acute infusion reactions Allergic/hypersensitivity reaction, arthralgia/myalgia, bronchospasm, cough, dizziness, drug fever, dyspnea, fatigue (asthenia, lethargy, malaise), headache, hypotension/ hypertension, nausea/vomiting, pruritus/itching, rash/desquamation, rigors/chills, sweating, tachycardia, onset or exacerbation of tumor pain, urticaria Grade 1: Mild reaction; infusion interruption not indicated; intervention not indicated Allergic reaction/hypersensitivity (including drug fever) Bronchospasm, wheezing, dyspnea, hypertension, hypotension, drug fever, edema/angioedema, flushing, rash, urticaria Common toxicity criteria Grade 1: Mild reaction; infusion interruption not indicated; intervention not indicated Grade 2: Requires therapy or infusion interruption but responds promptly to symptomatic treatment (e.g.,antihistamines, NSAIDs, narcotics, i.v. fluids); prophylactic medications indicated for 24hours Grade 3: Prolonged (i.e., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for other clinical sequelae (e.g., renal impairment, pulmonary infiltrates) Grade 4: Life threatening; pressor or ventilator support indicated Grade 5: Death Grade 1: Transient flushing or rash: drug fever<38 (<100.4 ) Grade 2: Rash; flushing; urticaria; dyspnea; drug fever 38 ( 100.4 ) Grade 3: Symptomatic bronchospasm with or without urticaria; parenteral medication(s) indicated; allergy-related edema/angioedema; hypotension Grade 4: Anaphylaxis Grade 5: Death 년 11월부터원내지침변경으로본용량투여전시험용량을투여하였고관찰기간중에는 49명만이시험용량투여후본용량을투여받았다. 또한관찰기간중 cetuximab의농도가 2 mg/ml에서 5 mg/ml로변경되었으며변경전제형은투여시 0.2~0.22 μm 크기의필터로여과하여투여하였으나변경후여과가필요하지않게되었으며 288명 (85.7%) 이제형변경이전에 cetuximab을투여받았다. 2. 주입관련반응의발생과양상주입관련반응을보인환자는 11명 (3.3%) 이었고이중 2명 (0.6%) 이중증에해당하였다. 주입관련반응의 - 15 -
JKSHP, VOL.30, NO.1 (2013) 증상은발진, 소양감등알레르기반응이가장많았고그외호흡곤란, 고열, 저혈압이발생하였다 (Fig. 1). 주입관련반응의정도는 1등급경증이 2명으로 18.2%, 2등급이 7명으로 63.6%, 4등급중증이 2명으로 18.2% 였다. 중증의경우 2초정도의식을소실한환자가 1명발생하였다 (Table 2). 투여차수에따른주입관련반응발생양상을보면대부분의환자가 1차투여에서발생하였지만 2차투여이후에도 2명이발생한것을확인할수있었다 (Table 3). 중증의환자 2명을포함한 7명 (2.5%), 항히스타민제 / 스테로이드제병용군 51명중 4명 (7.8%) 이주입관련반응을보였다 (p=0.63)(fig. 2). 4. 항암제병용여부에따른주입관련반응발생 Cetuximab 단독요법 84명중 4명 (4.8%), 병용요법 252명중 7명 (2.8%) 이주입관련반응을보였다 (p=0.712)(fig. 3). 3. 전처치약물에따른주입관련반응발생 전처치에서는항히스타민제단독사용군 285 명중 Table 3. 주입관련반응의중증도및 cetuximab 투여차수에따른발생환자수 중증도 1등급 ( 경증 ) 2등급 ( 중등도 ) 3등급 ( 중증 ) 투여차수 1차투여 2차투여이후 Fig. 1 주입관련반응의증상 2명 (18.2%) 7명 (63.6%) 2명 (18.2%) 9명 (81.8%) 2명 (18.2%) Table 2. 환자군의임상적특성 (n=336) 투여횟수 10.3회 (1-75) 연령 58세 (25-76) 성별남성 215명 (64.0%) 여성 121명 (36.0%) 신체계측키, cm 164.5(143-179) 체중, kg 60.3(42-93) 체표면적, m 2 1.69(1.35-2.11) 진단명대장암 293명 (87.2%) 두경부암 42명 (12.5%) 폐암 1명 (0.3%) Cetuximab 투여단독투여 84명 (25%) 병용투여 242명 (75%) 전처치항히스타민제 285명 (84.8%) 항히스타민제 / 스테로이드제 51명 (15.2%) 시험용량투여 49명 (14.6%) 투여하지않음 287명 (85.4%) 제형변경이전 288명 (85.7%) 이후 48명 (14.3%) - 16 -
장호석 : Cetuximab 주입관련반응의발생빈도및관련인자분석 5. 시험용량투여에따른주입관련반응의발생시험용량을투여받은군 49명중 5명 (10.2%), 투여받지않은군 287명중 6명 (2.1%) 이주입관련반응을보였다 (Fig. 4). 시험용량을투여받은군에서주입관련반응이발생한 5명중 3명은시험용량에서주입관련반응을예측할수없었고본용량투여시발생하였다. 6. 제형변경에따른주입관련반응의발생변경이전투여환자 288명중 2.1% 인 6명, 변경 Fig. 2 전처치약제에따른주입관련반응발생빈도 후 48명중 10% 인 5명이주입관련반응을보였다 (p=0.915). 고찰및결론본연구는단일기관을대상으로 cetuximab 투여시주입관련반응의발생빈도및관련인자를찾고자하였다. 주입관련반응발생빈도는 3.3%( 중증 0.6%) 로타보고에비해낮게나타났으며전처지약물및시험용량투여에대한유효성및주입관련반응을발생시키는유의한관련인자를찾기는어려웠다. 주입관련반응증상으로는발진, 가려움등경증의증상에서부터기관지경련, 저혈압, 호흡곤란등심각한증상을보인경우도있었다. 이는타약제의주입관련반응과유사했으며증증의증상이나타났을경우에는투약을중단해야하므로고가의약물이폐기되는등경제적손실을초래하였다. 또한, 이러한경제적손실뿐아니라주입관련반응치료에대한제반비용등을고려한손실에대해서도추후연구가필요할것으로보인다. MABEL 연구의 cetuximab과주입관련반응에대한추가적인분석에서전처치로항히스타민제와코르티코스테로이드제의병용이 1차투여에서주입관련반응의발생률을감소시킴을확인하였다. 이연구에서 cetuximab을투여받은전이성대장암환자 Fig. 3 타항암제병용여부에따른주입관련반응발생빈도 Fig. 4 시험용량투여에따른주입관련반응의발생 - 17 -
JKSHP, VOL.30, NO.1 (2013) 1122명중전처치약물로항히스타민제와코르티코스테로이드제병용군 (n=700) 을항히스타민제단독사용군 (n=422) 과비교하였을때주입관련반응의발생률이 3분의 1 수준으로감소하였으며 (9.6% vs 25.6%) 3등급이상의중증반응도 5분의 1 수준으로감소하였다 (1% vs 4.7%). 10,12) 비록본연구에서는전처치약물로항히스타민제와코르티코스테로이드제병용투여와주입관련반응발생률과의유의성은확인할수없었으나중증주입관련반응을보인 2명의환자는항히스타민제만투여한군이었다. 이는중증주입관련반응의경우에는전처치로항히스타민제와코르티코스테로이드제병용투여가유효할수있음을예측할수있다. 또한, 시험용량에대한앞선연구에서는 cetuximab 중증주입관련반응의약 90% 정도가 1차투여에서발생하며이에대한예측을위해 1차투여전에 20 mg의시험용량을투여하였지만무효하였다. 9) 이번연구에서도기존연구와마찬가지로 cetuximab 주입관련반응발생에대한시험용량투여의유효성은확인할수없었다. 그러나, 주입초기에나타날수있는주입관련부작용을확인하여이후투여시강력한전처치등의보조적인치료가가능할수있고중증의경우에는본용량투여를미룰수있는경제적이점이있으므로시험용량투여가전혀무효하다고할수는없다. 따라서본원에서는 cetuximab 투여시시험용량을투여하고있으며추후연구에서시험용량의필요성및경제적인효과를평가할필요가있다. 결론적으로본연구에서는주입관련반응발생률이기존문헌의보고보다훨씬낮은것을확인할수있었고낮은발생빈도로인해주입관련반응에대한유의한인자를찾기는어려웠다. 이는전자의무기록을바탕으로하였으므로경증의주입관련반응에대한누락의가능성을배제할수는없겠다. 또한전처치약물과시험용량에대한유효성을평가하기는어려웠다. 그러나전처치약물로항히스타민제와코르티코스테로이드제병용이전반적인주입관련반응을예방할수는없었으나중증의주입관련반응에는유효할수있음을확인하였고추후더많은환자들의경험을통해통계적인유의성을찾는것이중요하겠다. 참고문헌 1) Xue Song, Stacey R. Long, Beth Barber, et al.: Systemic Review on infusion reactions associated with chemotherapies and monoclonal antibodies for metastatic colorectal cancer, Curr Clin Pharmacol, 7, 56-65 (2012) 2) Chung C.H., Mirakhur B., Chan E., et al.: Cetuximab-induced anaphylaxis and IgE specific for galactose-a-1,3-galactose, N Engl J Med, 358, 1109-17 (2008) 3) Chung C.H., O Neil B.H. : Infusion reactions to monoclonal antibodies for solid tumors: Immunologic mechanisms and risk factors, Oncology 23(2Suppl 1), 14-7 (2009) 4) Lenz H.-J. : Management and preparedness for infusion and hypersensitivity reactions, The Oncologist, 12, 601-609 (2007) 5) Christine H. Chung : Managing premedications and the risk for reactions to infusional monoclonal antibody therapy, The Oncologist, 13, 725-732 (2008) 6) Dillman R.O. : Infusion reactions associated with the therapeutic use of monoclonal antibodies in the treatment of malignancy, Cancer Metastasis Rev, 18, 465-471 (1999) 7) US Food and Drug Administration. ErbituxTM (cetuximab): prescribing information[on line]. Available from URL:http://www.fda.gov/cder/foi/label/2 004/125084lbl.pdf. 8) Vermorken J.B., Trigo J., Hitt R., et al. : Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or - 18 -
장호석 : Cetuximab 주입관련반응의발생빈도및관련인자분석 metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy, J Clin Oncol, 25, 2171-2177 (2007) 9) Patel D.D., Goldberg R.M. : Cetuximab associated infusion reactions: pathology and management, Oncology, 20, 1373-1382 (2006) 10) Siena S., Glynne-Jones R., Adenis A., et al.: Reduced incidence of infusion-related reactions in metastatic colorectal cancer during treatment with cetuximab plus irinotecan with combined corticosteroid and antihistamine premedication, Cancer, 116(7), 1827-37 (2010) 11) National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0. Publish date August 9, 2006. Available at http://ctep.cancer.gov/ forms/ctcaev3.pdf. 12) Wilke H., Siena S., Thaler J., et al. : Impact of premediaction on the frequency of infusion related reactions (IRRs) and efficacy in patients (pts) treated with cetuximab plus irinotecan for metastatic colorectal cancer (mcrc): the MABEL study, Eur J Cancer, 5(4), 243 (2007) 13) American Pharmacists Association : Drug information handbook with international trade names index, 19th edition. 317-319 (2010-2011) - 19 -