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1 병원약사회지 (2018), 제 35 권제 2 호 J. Kor. Soc. Health-syst. Pharm., Vol. 35, No. 2, 177 ~ 183 (2018) Original Article 유방암환자에서의 trastuzumab 주입관련반응발생률및위험인자분석 정지혜 a, 김유진 a, 여미진 a, 박애령 a, 김순주 a, 황보신이 a, 나현오 b, 가톨릭대학교서울성모병원약제부 a, 가톨릭대학교약학대학 b Incidence and Risk Factors of the Infusion-Related Reactions in Breast Cancer Patients Receiving Trastuzumab Ji-Hye Jeong a, Yoo-Jin Kim a, Mi-Jin Yeo a, Ae-Ryoung Park a, Soon Joo Kim a, Shin-Yi Hwangbo a, and Hyen-O La b, Department of Pharmacy, The Catholic University of Korea Seoul ST. Mary s Hospital 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea a College of Pharmacy, The Catholic University of Korea 43 Jibong-ro, Bucheon-si, Gyeonggi-do, 14662, Republic of Korea b ABSTRACT Background : Trastuzumab is a monoclonal antibody for use in the treatment of the human epidermal growth factor receptor-2 (HER2) often overexpressed in breast cancer. One of its common side effects of this therapy use is the infusion-related reactions. Conversely, it is noted that there are no guidelines for preventing these side effects in patients. In this study, we aimed to find grounds to support the safe use of trastuzumab based on an analysis of the incidence and risk factor of the infusion-related reactions in breast cancer patients receiving trastuzumab. Methods : We evaluated the infusion-related reactions of the breast cancer patients receiving the first trastuzumab between Jan 1, 2014 and June 30, For the analysis of the risk factors, we collected the patient s information retrospectively using the access to the patient s secured electronic 투고일자 ; 심사완료일자 ; 게재확정일자 교신저자나현오 Tel: hola@catholic.ac.kr

2 JKSHP, VOL.35, NO.2 (2018) medical records. Results : In this study, a total of 91 patients were evaluated, and the total number of trastuzumab administration was with 270 cases. The infusion-related reactions were identified in 18 patients and the incidence was recorded at 19.8%. All infusion-related reactions were occurred during the first dose. And the symptoms began in the average timeframe of 76.5 minutes after the administration. The incidence of the infusion-related reactions was 11.1% in patients receiving premedication, and 21.9% in the patients not receiving the premedication (p=0.31). Particularly speaking, the patients who were weighing more than 70kg had a significantly higher risk of infusion-related reactions, than the patients who were known to weighing less than 70kg (odds ratio 5.23; 95% CI, ; P=0.01). And the higher patient's body mass index tended to occur more infusion-related reactions (odds ratio 1.15; 95% CI, ; P=0.08). Conclusion : Based on this result, in order to administer the trastuzumab safely, we suggest that the prevention guideline for the infusion-related reactions need to be utilized to consider the patient's body weight, and it is necessary to strengthen the monitoring to continue until the latter half of the drug therapy administration. [Key words] Trastuzumab, Infusion-related reactions, Breast cancer Trastuzumab은 human epidermal growth factor receptor-2 (HER2) 의세포외부분에결합하는단일클론항체로 HER2가과발현된조기, 전이성유방암의치료에사용된다. 1),2) Trastuzumab의작용기전은 HER2에결합하여세포내의 tyrosine kinase의활성을억제하고 HER2 수용체의수를감소시키며면역작동세포를결집시켜항체의존성세포독성을나타내는것이다. 3) HER2는유방암환자의 20-25% 에서과발현되어있다. 4)-6) HER2가과발현된유방암은공격적인임상양상을보이며빠른성장속도와전신전이, 무병생존율과전체생존율의감소와연관이있다고알려져있다. 4)-6) Trastuzumab은전이성유방암에서세포독성항암제와병용하여투여시무진행생존기간과반응률, 반응기간, 생존율에서세포독성항암제단독군에비해개선된효과를보였으며 7) 조기유방암에서는보조항암화학요법후 trastuzumab을투여한경우재발률의감 소와생존율의증가를보였다. 8),9) 대표적인부작용으로는심기능장애, 주입관련반응, 혈액독성, 감염및폐이상반응등이있다. 10) 주입관련반응은단일클론항체를주입중이거나주입후수시간이내에나타나는증상으로일반적으로경증에서중등증의증상을보이나심각한과민반응의증상이나타날수도있다. 11),12) 이러한반응의발생기전은명확하게밝혀지지않았으나, 혈중에서표적과반응하여염증성사이토카인이분비되어여러증상을나타내는것으로알려져있다. 1),11),13) Trastuzumab은 rituximab과더불어단일클론항체중주입관련반응의발생이높은약제중하나로약 40% 의환자에서첫투여시발생하고그중 1% 의환자에서는심각한증상이나타난다고알려져있다. 11) 주입관련반응의증상으로는발열, 오한과더불어오심, 구토, 통증, 두통, 어지러움, 호흡곤란, 저혈압, 발진, 무기력이나타나고심각한증상으로는기관지경련, 아나필락시스, 혈관부종등이보고되었다. 주입관련반응이발생하면 trastuzumab의주입을중단하거나주입속

3 정지혜 : 유방암환자에서의 trastuzumab 주입관련반응발생률및위험인자분석 도를감소시키고증상에따른증상완화제를투여하여치료할수있다. 10) 그러나주입관련반응의발생을낮추기위한전처치약제의사용등의지침은명확하지않고, 위험인자에관한연구는미국의 MD Anderson Cancer Center에서유방암환자를대상으로후향적연구가시행되었으나, 1) 국내에서는관련연구가부족하여추가적인연구가필요하다. 이에본연구에서는유방암의치료로 trastuzumab 을투여받은환자를대상으로주입관련반응의현황과영향을미치는위험인자를분석하여 trastuzuamab의안전한투약을위한지침을제시하고자하였다. 연구방법 1. 연구대상본연구는 2014년 1월부터 2015년 6월까지가톨릭대학교서울성모병원에서 trastuzumab 점적정맥주사투여를시작한 18세이상의여성유방암환자를대상으로하였다. 2. 자료수집및연구방법본연구는연구대상환자의 trastuzumab 투여시작후최대 3차투여까지의현황을조사하였고, 환자의기초정보 ( 연령, 성별, 체중, 체질량지수 (body mass index, BMI), 병기, 조직학적분류, 호르몬수용체상태 ) 와 trastuzumab 투여용량, 병용항암제종류, 투여된전처치약제, 주입관련반응의발생여부및증상, 발현시간에대한자료를전자의무기록 (electronic medical record) 을통하여후향적으로조사하였다. Trastuzumab으로인한주입관련반응의현황은주입관련반응발생현황과발생후대응방법에대해서조사하였다. 발생현황으로는발생률, 임상양상, 주입시작을기준으로한주입관련반응의발생시점에대해조사하였으며, 대응방법으로는주입관련반응발생후 trastuzumab의주입속도조절및주입중단여부와증상완화제투여와관련한내용을조사하였다. 주입관련반응에영향을미칠수있는위험인자를규명하기위하여체질량지수, 체중, 나이, 병기, 조직학적 분류, 호르몬수용체상태, 전처치약제의투여유무, 병용항암제의유무에따른주입관련반응발생위험에대해평가하였다. 본연구는가톨릭대학교서울성모병원윤리심사위원회 (institutional review board, IRB) 로부터연구계획서를심사받고, 시행허가를획득한후진행하였다 ( 과제번호 : KC15RISI0649). 3. Trastuzumab 투약스케줄 Trastuzumab은 3주요법과 1주요법으로투여되었다. 3주요법은 8 mg/kg의부하용량투여후유지용량은 6 mg/kg으로투여하였고, 1주요법은 4 mg/kg 의부하용량투여후 2 mg/kg으로투여하였다. Trastuzumab의주입시간은각요법의부하용량은 90분동안, 유지용량은진료과별프로토콜에따라 30 분혹은 60 분동안투여하였다. 4. 통계분석이연구의모든통계학적처리방법은 SAS Enterprise Guide 4 (SAS Institute, Inc, Cary, North Carolina) 를이용하였고위험인자분석을위해서단변량로지스틱회귀분석을사용하여오즈비를산출하였다. P value는 0.05 미만일때통계적유의성이있다고평가하였다. 연구결과 1. 대상환자의기본적특성연구기간내 trastuzumab을투여받은대상환자는총 91 명이었으며, 대상환자의병기는주로 I - III기이었고대부분의환자가침윤성유관암 (invasive ductal carcinoma) 이었다 (Table 1). Trastuzumab의총투여건수는 270건이었으며 91 명의환자중 90 명의환자가 3주요법으로투여하였다. 다른항암제와병용하여투여하는것보다 trastuzumab 을단독으로투여한경우가더많았으며, 전처치약제는투여하지않은환자가더많았다 (Table 2)

4 JKSHP, VOL.35, NO.2 (2018) Table 1 Patients characteristics (n=91) Mean (range) Age (years) 53.5(34-70) Weight (kg) 58.8( ) Body mass index 23.7( ) n (%) Stage Ⅰ 21(23.1) Ⅱ 33(36.2) Ⅲ 29(31.9) Ⅳ 8(8.8) Histological classification IDC * 83(91.2) ILC 4(4.4) Table 2 Treatment characteristics (n=270 cases) cases (%) Schedule Three-weekly 8 mg/kg 90(33.3) 6 mg/kg 177(65.6) Weekly 4 mg/kg 1(0.4) 2 mg/kg 2(0.7) Concurrent anticancer therapy Docetaxel 20(7.4) Paclitaxel 1(0.4) Doxorubicin / Paclitaxel 9(3.3) None (trastuzumab alone) 240(88.9) Premedication No 219(81.1) Yes 51(18.9) DCIS 1(1.1) Others 3(3.3) Receptor status ER positive 52(57.1) PR positive 36(39.6) HER2 ** positive 91(100) IDC*: invasive ductal carcinoma, ILC : invasive lobular carcinoma, DCIS : ductal carcinoma in situ, Others : mixed histologic subtype, invasive micropapillary carcinoma, ER : estrogen receptor, PR : progesterone receptor, HER2 ** : human epidermal growth factor receptor-2 Table 3 Incidence of infusion-related reaction (n=18) n (%) Number of administration 1st 18(19.8) 2nd 0(0) 3rd 0(0) Concurrent anticancer therapy Yes (n=11) 1(9.1) No (n=80) 17(21.3) 2. 주입관련반응발생현황 Trastuzumab 투여후주입관련반응의발생은 19.8%(18명 /91명) 으로모두 1차투여중발생하였고 trastuzumab 단독투여시와전처치약제를투여하지않은경우에발생률이높았다 (Table 3). 주입관련반응의임상양상의빈도는오한 13건, 발열 8건으로나타났으며, 그외에호흡곤란, 오심, 통증, 두통, 가슴답답함, 발진등이나타났다. 이들증상은복합적으로나타나는양상을보였다. Premedication Yes (n=18) 2(11.1) No (n=73) 16(21.9) 주입관련반응이발생한평균시간은 trastuzumab 주입후 76.5분이었다. Trastuzumab의첫번째투여시주입시간인 90분을기준으로주입후반부인 분사이에 13명 (72.2%) 의환자에서발생하였고, 1명

5 정지혜 : 유방암환자에서의 trastuzumab 주입관련반응발생률및위험인자분석 Fig. 1 Distribution of the initiation time of infusion-related reactions (n=18) Table 4 Univariate analysis of the study factors with infusion-related reactions Factor Contrast Odds ratio (95% CI) P Value Weight 70 kg vs. 70 kg 5.23( ) 0.01 BMI 1-unit increase 1.15( ) 0.08 Age 1-year increase 1.01( ) 0.65 Premedication Yes vs. no 0.45( ) Concurrent anticancer therapy Yes vs. no 0.371( ) ER status Positive vs. negative 0.7( ) PR status Positive vs. negative 0.97( ) (5.6%) 은주입시작후부터 45분사이에, 4명 (22.2%) 의환자는주입종료이후에발생하였다. 각환자별주입관련반응발생시간의분포는 (Fig. 1) 과같았다. 3. 주입관련반응발생시대응방법 Trastuzumab 투여후주입관련반응이발생한경우에 trastuzumab 주입중단과증상완화제투여로대응하였다. 주입관련반응이발생한 18명의환자중 12 명에서 trastuzumab 투여를중단하였고그중10명은증상이소실된후당일내재투여하였다. 주입관련반응으로인해 trastuzumab을영구중단한환자는없었 다. 증상완화제는환자가호소하는증상에따라진통제, 해열제, 항히스타민제, 항구토제등이투여되었다. 4. 위험인자분석주입관련반응발생에영향을미치는위험인자를분석하기위해체질량지수, 체중, 나이, 전처치약제의투여유무, 병용항암제유무, 호르몬수용체상태에따라주입관련반응발생의오즈비를산출하였다. 체중은 70 kg을기준으로 70 kg을초과하는환자가이하인환자보다 trastuzumab 투여후주입관련반응의발생위험이높게나타났다 (odds ratio 5.23; 95%

6 JKSHP, VOL.35, NO.2 (2018) CI, ; P=0.01). 체질량지수는값이 1 증가할수록주입관련반응의위험이증가하는경향을보였다 (odds ratio 1.15, 95% CI, , P=0.08). 나이와전처치약제의투여, 병용항암제유무, 호르몬수용체상태는주입관련반응발생에의미있는영향을미치지않았다 (Table 4). 고찰및결론 Trastuzumab은 HER2에작용하는단일클론항체로투여받는환자의약 21-40% 에서주입관련반응이발생한다. 10) 주입관련반응발생후의대응방법에대해서는허가사항에명시되어있으나, 주입관련반응발생전위험을낮추는방법에대한지침이나연구는부족한실정이다. 따라서본연구는 trastuzumab 투여시발생하는주입관련반응의현황및위험인자분석을통하여안전한투약을위한지침을마련하기위해시행되었다. 주입관련반응의평균발현시간은투여시작후 76.5 분이었다. Trastuzumab 주입중증상이나타난 14명중 60 분에서 90분사이에증상이발생한경우가 13명으로주로투여후반부에분포하였으며가장빠르게증상이나타난환자도주입후 43 분에주입관련반응이발생하였다. 이는투여후수분이내에나타나는 IgE가매개하는즉시형과민반응과는다른양상을보이며, 주입관련반응은투여종료시까지모니터링이필요한것으로보인다. Thompson 등의 197명의유방암환자를대상으로한 trastuzumab 투여후주입관련반응의발생률과위험인자분석에대한연구에서는주입관련반응발생률이 16.2% 로나타났고, 위험인자로는높은체질량지수, 병기 (IV기), 전처치약제의미투여가있었다. 1) Thompson 등과본연구는각각체질량지수와체중이주입관련반응의위험인자로분석되었다. Thompson 등의연구에서는체질량지수가 1이증가할수록주입관련반응이 1.09배증가하였고단변량분석에서는체질량지수가 29.9를초과한경우와이하인경우를비교하였을때의오즈비가 4.6 이었다. 본연구에서체질량지수는위험인자분석에서유의한결과를보이지는않았으나, 기준체중을 60 kg부터 5 kg단위로증가시켜기준체중이하와초과인환자를비교하여오 즈비를산출하였을때체중이 70 kg 초과인환자가이하인환자에비해주입관련반응의발생위험이 5.23배증가하였으며체중이 70 kg를초과하는환자의평균체질량지수는 28.9로두연구모두환자가비만일수록주입관련반응의위험이증가하는것으로나타났다. 단일클론항체에의한주입관련반응의정확한기전은밝혀지지않았으나사이토카인의분비와연관이있을것이라사료된다. 1),11) Rituximab 투여에관한연구에서는투여시작후 90분에측정한 tumor necrosis factor (TNF)-α와 interleukin (IL)-6의혈장농도가투여전보다높은수치를나타냈으며, 증가된사이토카인수치는발열, 오한과같은임상증상의발현과연관이있었다. 14) 이중 IL-6는지방세포를포함한다양한세포에서생성되며비만환자는지방세포에서더많은 IL-6가생성된다고알려져있다. 15) 추가적인연구가더필요하겠으나이는비만환자에서단일클론항체투여후주입관련반응이발생할위험이더높다는연구결과를뒷받침할수있는근거가될것으로사료된다. 본연구에서 trastuzumab의전처치약제의투여는임상의의의견에따라투여되어 18.9% 의환자가 trastuzumab 투여전전처치약제를투여받았다. 그러나위험인자분석에서기존의연구와는달리전처치약제의투여가주입관련반응을낮추는데유의한효과를나타내지는못하였다. 본연구의한계점으로는전자의무기록을바탕으로후향적연구가진행되어주입관련반응에영향이있는다른인자에대해고려하지못하였다는점과경증의주입관련반응에대한기록누락의가능성을배제할수없다는점이다. 본연구에서 trastuzumab 투여후주입관련반응은 19.8% 환자에서첫투약시, 투여중후반부에발생하였으며, 주로경증의증상이었다. 또한환자의체중이 70 kg을초과한경우가주입관련반응의위험인자로분석되었다. 따라서본연구의결과를바탕으로체중이 70 kg을초과하는환자를주입관련반응의고위험군으로분류하고 trastuzumab 초기투여시투여중후반까지모니터링을강화하는예방지침을수립한다면 trastuzumab을안전하게투여할수있을것으로사료된다

7 정지혜 : 유방암환자에서의 trastuzumab 주입관련반응발생률및위험인자분석 참고문헌 1) Thompson LM, Eckmann K, Boster BL et al. Incidence, risk factors, and management of infusion-related reactions in breast cancer patients receiving trastuzumab. Oncologist. 2014;19(3): ) Ross JS, Slodkowska EA, Symmans WF et al. The HER-2 receptor and breast cancer: Ten years of targeted anti-her-2 therapy and personalized medicine. Oncologist. 2009; 14(4): ) Hudis CA. Trastuzumab-mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1): ) Slamon D, Eiermann W, Robert N et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365: ) Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of relapse and survival with amplification of the HER- 2/neu oncogene. Science. 1987;235: ) Slamon DJ, Godolphin W, Jones LA et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244: ) Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344: ) Piccart-Gebhart MJ, Procter M, Leyland- Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353: ) Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353: ) Product Information: HERCEPTIN(R) intravenous infusion powder, trastuzumab intravenous infusion powder. Genentech, Inc. (per manufacturer), South San Francisco, CA, ) Chung CH. Managing premedications and the risk for reactions to infusional monoclonal antibody therapy. The Oncologist. 2008;13(6): ) Dillman RO. Infusion reaction associated with the therapeutic use of monoclonal antibodies in the treatment of malignancy. Cancer Metastasis Rev. 1999;18(4): ) Breslin S. Cytokine-release syndrome: overview and nursing implications. Clin J Oncol Nurs. 2007;11 Suppl 1: ) Winkler U, Jensen M, Manzke O et al. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-cd20 monoclonal antibody (rituximab, IDEC-C2B8). Blood. 1994:94(7): ) Bastard JP, Maachi M, Laqathu C et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw. 2006;17(1):

Jkbcs016(92-97).hwp

Jkbcs016(92-97).hwp Expression of bcl-2 and Apoptosis and Its Relationship to Clinicopathological Prognostic Factors in Breast Cancer - A Study with Long Term Follow-up correlated with the survival rate.(journal of Korean