Korean Journal of Clinical Oncology 2016;12: pissn eissn Original Article 유방암으로항암치료받는환자

Size: px

Start display at page:

Download "Korean Journal of Clinical Oncology 2016;12: pissn eissn Original Article 유방암으로항암치료받는환자"

미령 온
5 years ago
Views:

1 Korean Journal of Clinical Oncology 2016;12: pissn eissn Original Article 유방암으로항암치료받는환자에서발생하는과도한골수억제의예측인자 이정석, 이혜윤, 성낙송, 전기원, 문주익, 이상억, 최인석, 최원준, 윤대성 건양대학교의과대학외과학교실 Predictive factor for excessive myelosuppression in patients receiving chemotherapy for breast cancer Jung Suk Lee, Hye Yoon Lee, Nak Song Sung, Ki Won Cheon, Ju Ik Moon, Sang Eok Lee, In Seok Choi, Won Jun Choi, Dae Sung Yoon Department of Surgery, Konyang University Hospital, Konyang University Medicine School, Daejeon, Korea Purpose: Myelosuppression, particularly neutropenia, is one of the most frequent and serious toxicity seen in patients with breast cancer undergoing systemic chemotherapy. However, the predictive factors for development of severe neutropenia in chemotherapy remain unknown. We therefore evaluated predictive factors for excessive myelosuppression. Methods: We retrospectively analyzed 341 patients with breast cancer treated with chemotherapy from 2000 to Clinicopathological characteristics, number of using of granulocyte colony-stimulating factor (G-CSF), and pretreatment hematologic values were extracted from the electronic medical record system. Patients were sorted 2 groups by number of using G-CSF in each chemotherapeutic regimens; group 1 is more G-CSF (within high 20 percentile) and 2 less group (within lower 20 percentile). Results: Number of using G-CSF was ranged 0 83 (mean 10.76). One hundred one patients were in group 1 and 65 patients were in group 2. Mean of number of was 0.21 in group 1 and in group 2. Pretreatment white blood cell, hemoglobin and platelet count were lower in group 2 than in group 1 ( /μl vs /μl, g/dl vs g/dl, and μl vs μl). There were no statistically differences in other clinicopathologic characteristics such as age, body mass index or comorbidities, hormonal receptor, stage, and other pretreatment hematologic values. Conclusion: Pretreatment white blood cell count, hemoglobin and platelet count can be used to identify patients at increased risk of significant myelosuppression undergoing chemotherapy with breast cancer. This information can be used to target high-risk patients for prophylactic treatment. Keywords: Breast cancer, Myelosuppression, Granulocyte colony-stimulating factor, Chemotherapy 서론 Received: Apr 28, 2016 Accepted: Jun 9, 2016 Correspondence to: Hye Yoon Lee Department of Surgery, Konyang University Hospital, Konyang University College of Medicine, 158 Gwanjeodong-ro, Seo-gu, Daejeon 35365, Korea Tel: , Fax: hylee@kyuh.ac.kr Copyright Korean Society of Surgical Oncology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 유방암환자에서항암화학치료는주요한치료중의하나로재발방지및예후와생존율의향상에많은공헌을하고있다 [1,2]. 그러나이에따른부작용들도많다. 이들중, 골수억제, 특히호중구감소증은유방암으로항암화학치료를시행받는환자에서가장흔하고, 심각한부작용중의하나이며, 각종감염과관련된합병증을야기하고심한경우에는이로인해사망에까지이를수있는것으로알려져있다. 특히발열성호중구감소증 (absolute neutrophil counts lower than 500/mm 3 ) 은치료하지않을시에호중구성패혈증을유발할수있어서집중적인치료가필요하다. 또한치료의연기나중단및원 55

2 치않는항암제의감량등을초래하여궁극적으로환자의예후에도좋지않은영향을미칠수있다 [3,4]. 과립구집락자극인자는 DNA 재조합기술로만든것으로정상과립구전구세포의증식, 분화와성숙을자극, 촉진하여혈중호중구수치를높여면역력회복을도와준다. 또한과립구집락자극인자는호중구감소증에따른이러한부작용들을줄이기위해예방적으로사용하는약제로항암화학치료를시행하는환자들에서널리사용되고있으며예방적사용에대한항암화학요법및환자의특성에따른여러치료지침들이마련되었다 [5-8]. 그러나유방암으로항암화학치료를시행받는환자들에서심한백혈구감소증의예측인자에대해서는명확히밝혀져있지않다. 이에저자들은본연구에서과도한골수억제를예측할수있는인자들에관해알아보고자하였다. 방법 대상환자 2000 년부터 2012 년까지건양대학교병원에서수술전및수술후보조항암화학치료를시행받은 341 명의유방암환자를대상으로연구를진행하였다. 유방암에서주로사용되는항암화학요법 5 종류를선택하였으며, 그이외의항암화학요법을시행한환자 19 명을제외한 322 명을분석하였다. 총 322 명의환자중, 116 명의환자는 CMF (cyclophos phamide 100 mg 1 일차부터 14 일차까지복용, methotrexate 40 mg/m 2 과 5-fluorouracil 600 mg/m 2 을 1 일차와 8 일차에정맥주사, 4 주간격의방법으로총 6 차례시행 ), 97 명은 FAC (5-fluorouracil 500 mg/m 2 와 doxorubicin 50 mg/m 2 와 cyclophosphamide 500 mg/m 2 을 1 일차에정맥주사, 3 주간격의방법으로총 6 차례시행 ), 62 명은 AC 이후에 T (doxorubicin 60 mg/m 2 와 cyclophosphamide 600 mg/m 2 를 1 일차에정맥주사, 3 주간격으로총 4 차례시행후 paclitaxel 175 mg/m 2 을 1 일차에정맥주사 3 주간격으로총 4 차례시행 ), 19 명은 AC (doxo rubicin 60 mg/m 2 와 cyclophosphamide 600 mg/m 2 를 1 일차에정맥주사, 3 주간격으로총 4 차례시행 ), 28 명은 AD (doxorubicin 60 mg/m 2 와 docetaxel 75 mg/m 2 을 1 일차에정맥주사, 3 주간격으로총 6 차례시행 ) 로시행하였다. 모든환자는각항암제의표준요법에정해진횟수만큼시행할것으로계획하였다. 항암제시작전환자에게항암동의서를각각받았으며, 항암제투여하기 1 일전, 혹은항암제투여당일투여전에백혈구수, 혈소판수를비롯한기본혈액검사, 흉부 X 선촬영, 심전도를시행하였다. 항암제투여 1 일전혹은투여당일시행한혈액검사상호중구수 1,500 개 /μl 미만이거나, 혈소판 10 만 /μl 미만인경우에는항암제투여를 1 주일연기하였고, 2 번이상연기하게되는경우, 용량감량을 20% 시행하였다. 발열성호중구감소증이있는경우, 그다음항암제투여시에도용량감량을 20% 시행하였다. 항암제와동시에방사선치료및내분비치료를시행한환자는없었고, 필요한환자는항암제를모두마친후에시행하였다. 본연구는후향적연구로, 건양대학교병원임상시험센터의승인을받고 (IRB No.: ) 모든자료를전자차트를이용하여수 집하였다. 환자의나이, 키, 몸무게, 신체질량지수, 당뇨와고혈압등의동반질환의유무등의임상적특성및 tumor, node, metastasis (TNM) 병기와호르몬수용체등의조직학적특성과과립구집락자극인자의사용개수, 치료전혈액학적검사결과 ( 백혈구, 혈색소, 적혈구용적률, 혈소판, 신장기능, 간기능및혈당포함 ) 등을전자차트를이용하여수집하였다. 대상환자중항암화학요법시행전시행한혈액학적검사상 1,000 이하의절대호중구감소소견인경우과립구집락자극인자를사용하기시작하였으며, 절대호중구가 1,500 이상이되면투여를중지하였다. 과립구집락자극인자는필그라스팀 300 μg 을하루한번피하주사로사용하였다. 과립구집락자극인자의사용이많은환자군을상위 20 퍼센타일로보았고, 상위 20 퍼센타일에해당되는과립구집락자극인자사용횟수는 6 개이상이었다. 이와비교하기위해과립구집락자극인자사용이적은환자군을하위 20 퍼센타일에서확인하였고, 이는과립구집락자극인자사용횟수가 3 개이하로확인되었다. 그룹 1 을하위 20 퍼센타일환자군, 그룹 2 를상위 20 퍼센타일환자군으로설정하였다. 자료분석 통계학적인분석은 PASW ver (SPSS Inc., Chicago, IL, USA) 를이용하여, 과립구집락자극인자를적게사용한그룹 1 과많이사용한환자군인그룹 2 의임상병리학적요인과치료시작전혈액학적검사결과를 Fisher s exact 법을이용하여검정하였으며 P 값이 0.05 이하인경우를유의하다하였다. 또한안트라싸이클린항암제를사용한경우의그룹 1 과그룹 2 의치료시작전혈액학적검사결과에대해서도비교분석하였으며, 하위분석으로탁산계열항암제사용없이안트라싸이클린만사용한경우의그룹 1, 2 의혈액학적검사결과와안트라싸이클린과탁산계열항암제를동시또는연속적으로사용한경우의그룹 1, 2 의혈액학적검사결과를비교분석하였다. 결과 항암화학요법에따라골수억제정도의차이를보이기때문에유방암에서주로사용되는항암화학요법다섯종류를선택하였으며, 그이외의항암화학요법을시행한환자 19 명을제외한 322 명을분석하였다. 과립구집락자극인자를 3 개이하사용한그룹 1 환자는 101 명이었고, 6 개이상사용한그룹 2 환자는 65 명이었다. 두군간의나이및신체질량지수나동반질환, 호르몬수용체, TNM 병기는통계학적으로유의한차이를보이진않았다 (Table 1). 과립구집락자극인자의사용개수는평균 개 ( 범위, 0 83 개 ) 였으며, 과립구집락자극인자의사용개수가적은환자군인그룹 1 은평균 0.21 개를사용하였으며, 그룹 2 는평균 개를사용한것으로나타났다 (Table 1). 총 322 명의환자중 116 명의환자는 CMF (cyclophosphamide, methotrexate, 5-fluorouracil), 97 명은 FAC (5-fluorouracil, doxorubicin, and cyclophosphamide), 62 명은 AC T (doxorubicin and cyclophosphamide followed paclitaxel), 19 명은 AC, 28 명은 AD (doxorubicin and docetaxel) 요법을시행하였다 (Table 2). 항암화학요법에따라서도과 56 Korean Journal of Surgical Oncology

3 Jung Suk Lee et al. Predictive factor for myelosuppression in breast cancer Table 1. Patient demographics and tumor characteristics Characteristic Total (n= 322) (n = 101) (n= 65) b) Age (yr, mean) BMI (kg/m 2, mean) ER status 0.19 Positive 187 (58.1) 56 (55.4) 37 (56.9) Negative 129 (40.1) 40 (39.6) 28 (43.1) Unknown 6 (1.8) 5 (5.0) 0 PR status 0.60 Positive 170 (52.8) 53 (52.5) 32 (49.2) Negative 145 (45.0) 42 (41.5) 33 (50.8) Unknown 7 (2.2) 6 (6.0) 0 T stage 0.24 T1 142 (44.1) 42 (41.6) 36 (55.4) T2 128 (39.7) 45 (44.6) 22 (33.8) T3 11 (3.4) 4 (4.0) 0 T4 5 (1.6) 2 (2.0) 2 (3.1) N stage 0.12 N0 146 (45.3) 54 (53.5) 27 (41.5) N1 69 (21.4) 26 (25.7) 13 (12.9) N2 26 (8.1) 8 (7.9) 6 (9.2) N3 17 (5.3) 4 (4.0) 5 (7.7) No. of using G-CSF (mean) Comorbidity No 137 (42.5) 49 (48) 22 (34.4) Yes 185 (57.5) 53 (52) 42 (65.6) Values are presented as mean or number (%). BMI, body mass index; ER, estrogen receptor; PR, progesterone receptor; G-CSF, granulocyte colony-stimulating factor. 립구집락자극인자의사용개수는많은차이를보였으며 AD 요법을시행받는환자들에서평균 28 개 ( 범위, 0 60 개 ) 로가장많은과립구집락자극인자를사용하는것으로나타났다 (Table 2). 호중구감소증을동반한발열이한번이라도있었던환자는 Group 1 에서 5 명 (5.0%), Group 2 에서 6 명 (9.2%) 으로나타났고, 모든환자는안트라싸이클린포함항암화학요법으로치료받은환자였다. 과립구집락자극인자의사용개수가많았던그룹 2 환자군에서치료전백혈구수치가 5,970/μL 로 6,880/μL 인그룹 1 환자군에서보다유의하게낮았으며 (P = 0.007), 혈색소수치또한그룹 2 에서 g/dl 로그룹 1 의 g/dl 보다유의하게낮은것으로나타났다 (P = 0.009). 혈소판수치는그룹 2 에서 227,370/μL 로그룹 1 의 275,950/μL 보다유의하게낮았다 (P < 0.001). 이외의다른혈액학적검사수치는두군간의유의한차이를보이지않았다 (Table 3). 안트라싸이클린계열항암제를사용한환자군만따로그룹 1 과그룹 2 로나누어치료전혈액학적검사수치를비교분석하였고, 그룹 1 은 57 명, 그룹 2 는 41 명의환자가해당되었다. 혈액학적검사수치는백혈구수치가그룹 1 에서 6,920/μL, 그룹 2 에서 5,320/μL 로유의 Table 2. Grouping of patients by number of Chemotherapeutic agent No. of patient (n = 101) (n=65) b) CMF 116, 3.78 (0 50) 44, 0 24, 24 (6 50) FAC 97, 6.21 (0 52) 33, 0 20, 22 (10 52) AC P 62, 22 (0 83) 15, 0.93 (0 2) 12, (40 83) AD 28, 28 (0 60) 5, 1.4 (0 3) 5, 54.2 (50 60) AC 19, (0 51) 4, 0 4, 39 (34 51) Total 322, (0 51) 101, 0.21 (0 3) 65, (6 83) Values are presented as no. of, mean (range). G-CSF, granulocyte colony-stimulating factor; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; FAC, 5-fluorouracil, doxorubicin, cyclophosphamide; AC, doxorubicin, cyclophosphamide; P, paclitaxel; AD, doxorubicin, docetaxel. Table 3. Predictive factors of excessive myelosuppression in patients receiving chemotherapy for breast cancer (n = 101) (n=65) b) WBC count ( 10 3 μl) Neutrophil count (μl) 4, , Hemoglobin (g/dl) Hematocrit (%) PLT count ( 10 4 μl) Glucose AST/ALT (IU/L) 23.2/ / /0.815 BUN/Cr 15.8/ / /0.119 Protein/albumin 7.29/ / /0.120 G-CSF, granulocyte colony-stimulating factor; WBC, white blood cell; PLT, platelet; AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN/Cr, blood urea nitrogen/creatinine. 하게그룹 2 에서낮은것으로나타났고 (P = 0.007), 혈소판수치가그룹 1 에서 280,410/μL, 그룹 2 에서 230,080/μL 으로나타나이역시그룹 2 에서유의하게낮은것으로나타났다 (P = 0.001). 혈색소수치나다른혈액학적검사소견은유의한차이를보이지않았다 (Table 4). 탁산계열항암제를사용하지않고안트라싸이클린항암제만사용한경우인, FAC 요법과 AC 요법을사용한환자 61 명에대해하위분석을시행한결과호중구수치는그룹 1 에서 4,927/μL, 그룹 2 에서 3,645/μL 로그룹 2 에서유의하게낮은것으로나타났고 (P = 0.009), 혈소판수치또한그룹 1 에서 273,680/μL, 그룹 2 에서 226,190/μL 로, 그룹 2 에서유의하게낮은것으로나타났다 (P = 0.014). 백혈구, 혈색소등의다른혈액학적검사는두그룹간의유의한차이를보이지않았다 (Table 5). 안트라싸이클린항암제와탁산계열항암제를동시또는연속해서사용한경우인, AC-P 요법과 AD 요법항암제를사용한 37 명의 57

4 Table 4. Predictive factors of excessive myelosuppression in patients receiving anthracycline based chemotherapy for breast cancer 환자에대해그룹 1, 2 로나누어혈액학적검사를비교분석한결과, 백혈구, 호중구, 혈색소, 혈소판등모든혈액학적검사결과에서유의한차이를보이지않았다. 고찰 (n= 57) (n= 41) b) WBC count ( 10 3 μl) Neutrophil count (μl) 4, , Hemoglobin (g/dl) Hematocrit (%) PLT count ( 10 4 μl) Glucose AST/ALT (IU/L) 21.2/ / /0.789 BUN/Cr 15.7/ / /0.120 Protein/albumin 7.29/ / /0.120 G-CSF, granulocyte colony-stimulating factor; WBC, white blood cell; PLT, platelet; AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN/Cr, blood urea nitrogen/creatinine. 항암화학요법의부작용중의하나인골수억제는발열이동반되면서호중구를감소시켜사용중인항암제용량을감량해야하는주요인이다. 이와같은환자는비록임상증상의발현이없더라도즉각적인항생제치료를하지않을경우세균감염과관련한합병증및사망을초래할수있으며, 치료의연기나중단및원치않는항암제의감량등을초래하여궁극적으로환자의예후에도좋지않은영향을미칠수있다 [3,4]. 열성호중구감소증의위험도는기간과정도에비례하며, 특히그람음성균혈증의경우항생제치료를즉시하지않으면급속히나빠질수있기때문에광범위항생제투여를함으로써환자의사망률을낮출수있다. 또한열성호중구감소증의위험인자로는항암제의종류, 투여용량, 환자의나이, 암의종류및동반질환등이있다. 열성호중구감소증환자들은자주입원하기때문에삶의질이저하되며여러감염에의한합병증과동반질환이악화될수있다. 주사망원인은패혈증, 패혈증쇼크와폐렴이며사망률이 0% 20% 까지보고되고있다 [6]. 과립구집락자극인자는호중구감소증에따른이러한부작용들을줄이기위해예방적으로사용하는약제로항암화학요법을시행하는환자들에서널리사용되고있으며예방적사용에대한항암화학요법및환자의특성에따른여러치료지침들이마련되었다. 이지침들에서는 65 세이상의고령, 수행능력저하및영양상태불량, 과거에절대호중구수치감소증및항암화학요법과거력이있는경 Table 5. Predictive factors of excessive myelosuppression in patients receiving FAC and AC chemotherapy for breast cancer (n=37) (n=24) b) WBC count ( 10 3 μl) 7, 18 6, Neutrophil count (μl) 4, , Hemoglobin (g/dl) Hematocrit (%) PLT count ( 10 4 μl) Glucose AST/ALT (IU/L) 22.8/ / /0.670 BUN/Cr 12.7/ / /0.607 Protein/albumin 7.25/ / /0.184 FAC, 5-fluorouracil, doxorubicin, cyclophosphamide; AC, doxorubicin, cyclophosphamide; G-CSF, granulocyte colony-stimulating factor; WBC, white blood cell; PLT, platelet; AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN/Cr, blood urea nitrogen/creatinine. 우에예방적으로과립구집락자극인자를사용할수있다 [5-8]. 본원에서도항암화학요법을시행하는환자들중에서절대호중구수치감소증및항암제용량감소인경우에예방적으로과립구집락자극인자를사용하였으며, 사용횟수는 0 83 회로항암약제의종류및환자의특성에따라다양하였다. 따라서과립구집락자극인자의사용횟수에따라골수억제의정도를분류하여골수억제의예측인자를분석하고자하였다. 몇몇연구에서과도한골수억제및발열성호중구감소증에대한예측인자로과립구집락자극인자의지침에서와유사하게 65 세이상, 진행된병변, 골수침범, 빈혈, 이전치료및항암방사선치료의병합요법, 신병변을비롯한동반질환, 환자의수행능력과첫번째항암화학요법후절대호중구감소등을발표한바있다 [3,4,9,10]. 본연구에서도이미발표된바와같이항암화학요법의종류에따라골수억제의정도에서차이를보였다. 항암화학요법중에서안트라싸이클린을포함하는 AD 및 AC 복합요법에서강력한골수억제를보였다. 또한치료전백혈구및혈색소와혈소판수치가낮았던환자들에서과립구집락자극인자를많이사용하였다. 본연구에서는나이및신체질량지수나당뇨와고혈압등의동반질환은골수억제의정도에영향을미치지않는것으로나타났으며, 유방암의병기나호르몬수용체와같은종양의특성과간기능및신장기능과혈당과같은혈액학적검사결과는골수억제의예측인자로의미가없었다. 하지만환자의수가적어제한적이며, 골수억제의정도를과립구집락자극인자의사용개수로만구분하여분석했다는점에서한계가있으며선택편견이작용했을것으로추측된다. 따라서이를극복하기위해서는추가적인연구가시행되어야할것으로생각된다. 결론적으로, 본연구에서유방암환자에서항암화학요법을시행 58 Korean Journal of Surgical Oncology

5 Jung Suk Lee et al. Predictive factor for myelosuppression in breast cancer 하기전백혈구, 혈색소, 혈소판수치가낮은환자들은골수억제의고위험군으로나타났으며, 안트라싸이클린과탁산을포함하는항암요법을시행한환자군에서심한골수억제를보였다. 따라서이러한환자들을고위험군으로분류하여예방적으로과립구집락자극인자를사용함으로써과도한골수억제를예방할수있을것으로생각되며, 예측인자에대한추가적인연구가필요할것으로생각된다. CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. Renner P, Milazzo S, Liu JP, Zwahlen M, Birkmann J, Horneber M. Primary prophylactic colony-stimulating factors for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients. Cochrane Database Syst Rev 2012;10:CD Garg P, Rana F, Gupta R, Buzaianu EM, Guthrie TH. Predictors of toxicity and toxicity profile of adjuvant chemotherapy in elderly breast cancer patients. Breast J 2009;15: Jenkins P, Freeman S. Pretreatment haematological laboratory values predict for excessive myelosuppression in patients receiving adjuvant FEC chemotherapy for breast cancer. Ann Oncol 2009;20: Rivera E, Haim Erder M, Fridman M, Frye D, Hortobagyi GN. First-cycle absolute neutrophil count can be used to improve chemotherapy-dose delivery and reduce the risk of febrile neutropenia in patients receiving adjuvant therapy: a validation study. Breast Cancer Res 2003;5:R Silvestris N, Del Re M, Azzariti A, Maiello E, Lombardi L, Cinieri S, et al. Optimized granulocyte colony-stimulating factor prophylaxis in adult cancer patients: from biological principles to clinical guidelines. Expert Opin Ther Targets 2012;16 Suppl 2:S Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, et al update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 2011;47: Procopio G, Niger M, Testa I. Lecture: management of chemotherapy-induced febrile neutropenia; guidelines and colony stimulating factors. Neurol Sci 2011;32 Suppl 2:S Zhu X, Bouganim N, Vandermeer L, Dent SF, Dranitsaris G, Clemons MJ. Use and delivery of granulocyte colony-stimulating factor in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy-single-centre experience. Curr Oncol 2012;19:e Chen C, Chan A, Yap K. Visualizing clinical predictors of febrile neutropenia in Asian cancer patients receiving myelosuppressive chemotherapy. J Oncol Pharm Pract 2013;19: Weycker D, Edelsberg J, Kartashov A, Barron R, Lyman G. Risk and healthcare costs of chemotherapy-induced neutropenic complications in women with metastatic breast cancer. Chemotherapy 2012;58:

( )Jkstro011.hwp

( )Jkstro011.hwp 비인강암의방사선치료결과및생존율에관한예후인자분석 2005 2 1 2005 3 28. :, Tel: 053)250-7665, Fax: 053)250-7984 E-mail: jhkim@dsmc.or.kr 정영연외 2 인 : 비인강암의예후인자분석 정영연외 2 인 : 비인강암의예후인자분석 Carcinoma of the nasopharynx treated by radiotherapy