병원약사회지 (2021), 제 38 권제 1 호 J. Kor. Soc. Health-syst. harm., Vol. 38, No. 1, 6 ~ 17 (2021) https://doi.org/10.32429/jkshp.2021.38.1.001 Original Article 전이성직결장암환자에서원발병소위치에따른 Cetuximab 과 Bevacizumab 의치료효과비교분석 김유진, 안혜림, 권은영 가톨릭대학교서울성모병원약제부 Analysis of Therapeutic Effects of Cetuximab and Bevacizumab Related to the rimary Tumor Site in atients with Metastatic Colorectal Cancer Yoo Jin Kim, Hye Lim Ahn, Eyn Young Kwon Department of harmacy, Seoul St. Mary s Hospital, The Catholic University of Korea 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea Background : Recent reports on metastatic colorectal cancer (mcrc) demonstrated that the primary tumor origin site was related to significantly different effects of biologic therapy (BT). However, in the Korean clinical field, patients are still prescribed cetuximab regardless of the primary tumor site. Therefore, it is necessary to determine whether there is a different response to BT in Korean patients as well. This study analyzed the correlation between the effect of BT and the primary tumor origin in patients with mcrc. Methods : This study included all patients diagnosed with mcrc from January 1, 2015, through December 31, 2016, who were treated with first-line chemotherapy containing bevacizumab or cetuximab. We followed the patients using EMR analysis until September 30, 2018. We compared the different effects of BT based on the primary tumor site by the time to progression (TT) and the overall response rate (ORR). Results : One hundred and sixty-one patients were eligible for the study, 50 patients had 투고일자 2020.8.17; 심사완료일자 2020.10.19; 게재확정일자 2020.12.16 교신저자김유진 Tel:02-2258-2562 E-mail:flpst4u@cmcnu.or.kr - 6 -
김유진 : 전이성직결장암환자에서원발병소위치에따른 Cetuximab 과 Bevacizumab 의치료효과비교분석 right-sided primary tumor origins and 111 patients had tumors on the left. Among patients who received bevacizumab, there was no significant difference regardless of the primary tumor site, whereas, in patients treated with cetuximab, left-sided mcrc was related to longer TT compared to right-sided (hazard ratio [HR]=1.92, 95% CI: 0.98 3.60; p=0.050). In other words, there was no significant difference between bevacizumab and cetuximab in the left-sided mcrc patients. However, in the right-sided mcrc patients, bevacizumab showed a significantly improved TT compared to cetuximab (HR=2.08, 95% CI: 1.03 4.03; p=0.036). Conclusion : The primary tumor site was related to the response to BT in patients with mcrc. Right-sided primary tumor origin was associated with significantly improved TT when treated with bevacizumab compared to cetuximab. Therefore, we recommend considering not only the molecular status but the primary tumor site when choosing BT for mcrc patients in the future. [Key words] Metastatic colorectal cancer, Right/left side primary tumor, Bevacizumab, Cetuximab, TT, ORR 전이성직결장암에서원발병소의위치는중요한예후인자로알려져있다. 1)-3) 해부학적으로직결장은맹장에서부터횡행결장의 2/3 지점까지를오른쪽으로, 나머지횡행결장의 1/3 지점부터직장까지를왼쪽으로구분한다. 4) 원발병소가오른쪽에위치한경우조기진단이어렵고불량한예후인자인 KRAS, BRAF 돌연변이와 microsatellite instability-high (MSI-H) 의발현빈도가높기때문에, 4)-6) 왼쪽에위치한경우보다일반적으로예후가좋지않다고알려져있다. 1),2) 또한, Fotios Loupakis et al., rice TJ et al., Sebastian Stintzing et al. 의선행연구에서도직결장암에서사용되는보편적인 systemic chemotherapy 진행시원발병소가왼쪽인환자에서더개선된 progression free survival (FS), overall survival (OS) 결과를보였다. 2)-4) 현재 National Comprehensive Cancer Network (NCCN) guideline과국내직결장암치료지침에서는전이성직결장암환자에게 systemic chemotherapy에생물학적치료제를함께사용하는것을권장하고있다. 직결장암에서사용되는생물학적치료제는크게 vascular endothelial growth factor (VEGF) 와 epidermal growth factor receptor (EGFR) 에대한단일클론항체약제로나눌수있다. 먼저 bevacizumab (Avastin ) 은 VEGF에결합하여신생혈관의형성을저해함으로항암효과를나타내며, 현재우리나라에서는전이성직결장암, 비소세포폐암, 난소암등에서사용되는데특히전이성직결장암에서는고식적치료요법 1차와 2차로사용할때보험급여가인정되고있다. Cetuximab (Erbitux ) 은 anti-egfr monoclonal antibody로세포의성장, 분화및생존을억제하여전이성직결장암과두경부암에효과가있으며, 전이성직결장암에서는고식적치료요법 1차에보험급여인정되고있다. 최근의연구들에따르면 systemic chemotherapy에단순히생물학적치료제를추가하는것에서더나아가생물학적치료제의항암효과도원발병소의위치에따라차이가있다는연구결과가보고되고있다. 7)-9) 원발병소의위치가왼쪽 ( 이하, 좌측직결장암 ) 인환자에서는 bevacizumab과 cetuximab의약효가통계적으로유의한차이가없고오른쪽 ( 이하, 우측직결장암 ) 인환자에서 bevacizumab이 cetuximab보다유의한사망률, OS, FS 개선을보인연구가있었으며, 7)-9) RAS 정상형인전이성직결장암환자만비교하였을때좌측직결장암환자에서 - 7 -
JKSH, VOL.38, NO.1 (2021) Fig. 1 Schematic diagram of left- and right-sided regions of the colon and rectum 4) 는 bevacizumab 보다 cetuximab이, 우측직결장암환자에선 cetuximab보다 bevacizumab이사망률, OS, overall response rate (ORR), FS의개선효과가우수하였다는연구결과도있다. 7)-10) 이러한결과를바탕으로 NCCN guideline에서는 KRAS/NRAS 정상형이면서원발병소의위치가왼쪽인전이성직결장암의경우에만 anti-egfr therapy (cetuximab, panitumumab) 를권고하고있다. 그러나현재까지본원에서는원발병소의위치와무관하게 cetuximab을사용하고있으며, NCCN guideline discussion에서도향후더연구가필요하다고밝히고있으므로실제국내환자를대상으로이러한효과차이가존재하는지확인할필요가있다. 이에본연구에서는국내전이성직결장암환자를대상으로원발병소의위치에따른 bevacizumab과 cetuximab의효과를비교분석하고자하였다. 화학요법을고식적치료요법 1차로시행한전이성직결장암환자를대상으로하였고, 2018년 9월까지관찰하였다. 외국인환자, 원발병소위치가불명확하거나 2개이상인환자, 항암화학요법시행후원내에서추적관찰하지않은환자는연구대상에서제외하였다. 2. 자료수집및연구방법환자의전자의무기록을통하여후향적으로검토하였으며, 본연구는서울성모병원임상시험심사위원회의승인하에진행되었다 ( 과제번호 KC18RESI 0479). 수집내용으로는항암화학요법시작시점의진료기록을통해대상환자의성별, 연령, 원발병소의위치, 전이된장기의수, 이전항암화학요법시행유무및종류, 수술여부, bevacizumab/cetuximab 포함항암화학요법의종류, EGFR 발현여부, KRAS, NRAS 돌연변이여부를포함하였다. 연구방법 1) 원발병소의위치분류 1. 연구대상가톨릭대학교서울성모병원 ( 이하서울성모병원 ) 외래및입원환자중 2015년 1월부터 2016년 12월까지 bevacizumab 혹은 cetuximab이포함된항암 원발병소의해부학적위치에따라분류하였으며, 4) 원발병소위치가맹장에서부터상행결장, 간만곡부 (hepatic flexure), 횡행결장까지를우측직결장암으로, 비장굴곡 (splenic flexure) 부터하행결장, 직장-S상결장이음부, 직장까지를좌측직결장 - 8 -
김유진 : 전이성직결장암환자에서원발병소위치에따른 Cetuximab 과 Bevacizumab 의치료효과비교분석 암으로정의하여비교하였다 (Fig. 1). 연구결과 2) Bevacizumab/Cetuximab 포함항암화학요법의효과평가 (1) 질병진행까지의기간 (Time To rogression, TT) Bevacizumab/Cetuximab 포함항암화학요법의시작일로부터질병진행판정을받을때까지의기간을 TT로정의하여비교하였다. (2) 전체반응률 (Overall Response Rate, ORR) 치료반응은일정기간마다실시된 computed tomography (CT) scan이나 magnetic resonance imaging (MRI) 을통하여 Response Evaluation Criteria In Solid Tumors (RECIST) 기준에따라전문의의판단에의해평가되었다. 각환자의치료시작후 12개월시점의반응평가가완전반응 (complete response, CR) 과부분반응 (partial response, R) 인경우의합을 ORR로정의하여비교하였으며, 이시점에이미사망하였거나추적관찰에서누락된환자는제외하였다. 3. 자료분석대상환자군특성이연속형변수인경우에는 Wilcoxon rank sum test를, 범주형변수인경우에는 Chi-square test를시행하여비교하였다. 원발부위의위치와 bevacizumab/cetuximab 의효과간의상관관계는먼저각군의 TT 값을 Kaplan Meier survival plots으로보고 logrank test로유의성을검증하였으며, 추가적으로 TT는 cox proportional hazard regression analysis의 hazard ratio를통해, ORR은 logistic regression anlaysis의 odds ratio를통해비교하였다. 모든분석에는 SAS software, version 9.4 (SAS Institute Inc., Cary, NC) 을사용하였고, p값이 0.05 미만인경우를유의한것으로판단하였다. 1. 환자특성 2015년 1월부터 2016년 12월까지가톨릭대학교서울성모병원에서 bevacizumab/cetuximab 포함항암화학요법을고식적치료요법 1차로투여받은전이성직결장암환자 165명중연구대상기준을충족하는총 161명의환자를대상으로연구를실시하였으며, 평균추적기간은 56주였다. 대상환자군의특성은 Table 1, Table 2와같았다. 원발병소가오른쪽이면서 bevacizumab을투여한환자는 36명, cetuximab을투여한환자는 14 명이었고, 원발병소가왼쪽이면서 bevacizumab 을투여한환자는 72명, cetuximab을투여한환자가 39명이었다. 각비교군에따라유의한차이를보이는항목이달랐으며, bevacizumab 투여군에서원발위치에따라나이 (right 64.4±9.5 vs left 59.8±11.0; p=0.037) 와이전항암화학요법시행유무 (right 5 [13.9%] vs left 32 [44.4%]; p=0.002) 에서유의한차이를보였다. 반면, cetuximab 투여군에서는원발위치에따라유의한차이가없었다. 또한우측직결장암환자군에서는약제종류에따라나이 (bevacizumab 64.4±9.5 vs cetuximab 57.9 ±8.9; p=0.031) 가, 좌측직결장암환자군에서는성별 (bevacizumab male 38 [52.8%] vs cetuximab male 29 [74.4%]; p=0.027) 이유의하게달랐다. 2. Bevacizumab/Cetuximab을포함항암화학요법의약효평가 1) 질병진행까지의기간 (Time To rogression, TT) 동일한생물학적치료제를투여한환자군에서원발병소위치에따른약효를 TT로비교해보면, bevacizumab 투여군에서는원발병소위치에따라약효의유의한차이가없었다. 하지만 cetuximab 투여군에서는좌측직결장암인경우가우측직결장암인 - 9 -
JKSH, VOL.38, NO.1 (2021) Table 1 atients characteristics (treatment type within strata of tumor site) Bevacizumab (n=36) Right Cetuximab (n=14) Bevacizumab (n=72) Left Cetuximab (n=39) Age Mean±SD 64.4 ± 9.5 57.9 ± 8.9 0.031 59.8 ± 11.0 61.4 ± 10.5 0.468 Median (range) 62.5 (49-83) 59 (44-68) 60.5 (22-79) 61 (38-81) Gender, n (%) Male 17 (47.2) 10 (71.4) 0.123 38 (52.8) 29 (74.4) 0.027 Female 19 (52.8) 4 (28.6) 34 (47.2) 10 (25.6) No. metastasis, n (%) 1 29 (80.6) 10 (71.4) 0.639 53 (73.6) 31 (79.5) 0.856 2 4 (11.1) 2 (14.3) 16 (22.2) 7 (17.9) 3 3 (8.3) 2 (14.3) 3 (4.2) 1 (2.6) Metastasis, n (%) Lung 9 (25.0) 3 (21.4) >0.999 33 (45.8) 11 (28.2) 0.070 Liver 18 (50.0) 9 (64.3) 0.363 33 (45.8) 25 (64.1) 0.066 Brain 0 (0.0) 0 (0.0) - 2 (2.8) 0 (0.0) 0.540 Bone 4 (11.1) 0 (0.0) 0.566 4 (5.6) 1 (2.6) 0.655 Other 16 (44.4) 8 (57.1) 0.420 18 (25.0) 9 (23.1) 0.822 Molecular status, n (%) EGFR, positive (n=157) R-B=34, L-B=70, R-C=14, L-C=39 KRAS, mutation (n=158) R-B=35, L-B=70, R-C=14, L-C=39 NRAS, mutation (n=139) R-B=25, L-B=61, R-C=14, L-C=39 BRAF, wild type (n=36) R-B=7, L-B=17, R-C=2, L-C=10 25 (73.5) 14 (100.0) 0.043 51 (72.9) 39 (100.0) <0.001 29 (82.9) 0 (0.0) <0.001 51 (72.9) 0 (0.0) <0.001 1 (4.0) 0 (0.0) >0.999 5 (8.2) 0 (0.0) 0.153 7 (100.0) 2 (100.0) - 17 (100.0) 10 (100.0) - MSI test (n=67) R-B=9, L-B=33, R-C=5, L-C=20 MSS 9 (100.0) (100.0) - 32 (97.0) 20 (100.0) >0.999 MSI-low 0 (0.0) 0 (0.0) 1 (3.0) 0 (0.0) Surgical, alliative O*, n (%) 24 (66.7) 9 (64.3) >0.999 44 (61.1) 27 (69.2) 0.395 History of chemotherapy, n (%) 5 (13.9) 2 (14.3) >0.999 32 (44.4) 13 (33.3) 0.255-10 -
김유진 : 전이성직결장암환자에서원발병소위치에따른 Cetuximab 과 Bevacizumab 의치료효과비교분석 Right Left Bevacizumab (n=36) Cetuximab (n=14) Bevacizumab (n=72) Cetuximab (n=39) History of chemotherapy regimen (n=52) FOLFOX 4 (80.0) 2 (100.0) 10 (31.3) 4 (30.8) Capecitabine, oxaliplatin 0 (0.0) 0 (0) 1 (3.1) 0 (0) 5-Fluorouracil, leucovorin 1 (20.0) 0 (0) 17 (53.1) 8 (61.5) Capecitabine 0 (0.0) 0 (0) 4 (12.5) 1 (7.7) O*: operation, FOLFOX : 5-Fluorouracil, leucovorin, oxaliplatin Data are presented as the n (%) for categorical variable, unless otherwise indicated. for difference were determined by using chi-square or the wilcoxon rank sum test. Table 2 atients characteristics (right vs left sides within strata of treatment type) Bevacizumab (n=108) Cetuximab (n=53) Right (n=36) Left (n=72) Right (n=14) Left (n=39) Age Mean±SD 64.4 ± 9.5 59.8 ± 11.0 0.037 57.9 ± 8.9 61.4 ± 10.5 0.264 Median (range) 62.5 (49-83) 60.5 (22-79) 59 (44-68) 61 (38-81) Gender, n (%) Male 17 (47.2) 38 (52.8) 0.586 10 (71.4) 29 (74.4) >0.999 Female 19 (52.8) 34 (47.2) 4 (28.6) 10 (25.6) No. metastasis, n (%) 1 29 (80.6) 53 (73.6) 0.315 10 (71.4) 31 (79.5) 0.255 2 4 (11.1) 16 (22.2) 2 (14.3) 7 (17.9) 3 3 (8.3) 3 (4.2) 2 (14.3) 1 (2.6) Metastasis, n (%) Lung 9 (25.0) 33 (45.8) 0.036 3 (21.4) 11 (28.2) 0.735 Liver 18 (50.0) 33 (45.8) 0.683 9 (64.3) 25 (64.1) 0.990 Brain 0 (0.0) 2 (2.8) 0.551 0 (0.0) 0 (0.0) - Bone 4 (11.1) 4 (5.6) 0.437 0 (0.0) 1 (2.6) >0.999 Other 16 (44.4) 18 (25.0) 0.040 8 (57.1) 9 (23.1) 0.042-11 -
JKSH, VOL.38, NO.1 (2021) Bevacizumab (n=108) Cetuximab (n=53) Right (n=36) Left (n=72) Right (n=14) Left (n=39) Molecular status, n (%) EGFR, positive (n=157) R-B=34, L-B=70, R-C=14, L-C=39 KRAS, mutation (n=158) R-B=35, L-B=70, R-C=14, L-C=39 NRAS, mutation (n=139) R-B=25, L-B=61, R-C=14, L-C=39 BRAF, wild type (n=36) R-B=7, L-B=17, R-C=2, L-C=10 25 (73.5) 51 (72.9) 0.942 14 (100.0) 39 (100.0) - 29 (82.9) 51 (72.9) 0.257 0 (0.0) 0 (0.0) - 1 (4.0) 5 (8.2) 0.667 0 (0.0) 0 (0.0) - 7 (100.0) 17 (100.0) - 2 (100.0) 10 (100.0) - MSI test (n=67) R-B=9, L-B=33, R-C=5, L-C=20 MSS 9 (100.0) (100.0) - 32 (97.0) 20 (100.0) >0.999 MSI-low 0 (0.0) 0 (0.0) 1 (3.0) 0 (0.0) Surgical, alliative O*, n (%) 24 (66.7) 44 (61.1) 0.573 9 (64.3) 27 (69.2) 0.748 History of chemotherapy, n (%) 5 (13.9) 32 (44.4) 0.002 2 (14.3) 13 (33.3) 0.300 History of chemotherapy regimen (n=52) FOLFOX 4 (80.0) 10 (31.3) 2 (100.0) 4 (30.8) Capecitabine, oxaliplatin 0 (0.0) 1 (3.1) 0 (0) 0 (0) 5-Fluorouracil, leucovorin 1 (20.0) 17 (53.1) 0 (0) 8 (61.5) Capecitabine 0 (0.0) 4 (12.5) 0 (0) 1 (7.7) O*: operation, FOLFOX : 5-Fluorouracil, leucovorin, oxaliplatin Data are presented as the n (%) for categorical variable, unless otherwise indicated. for difference were determined by using chisquare or the wilcoxon rank sum test. 경우보다 TT가연장되어질병진행이느려지는경향을보였다 (hazard ratio [HR]=1.92, 95% CI: 0.98-3.60; p=0.050)(fig. 2)(Table 3). 각원발병소에서생물학적치료제에따라약효를비교하면우측직결장암의경우, bevacizumab 군에서 cetuximab 군보다 TT가유의하게연장되었다 (HR=2.08, 95% CI: 1.03-4.03; p=0.036). 반면좌측직결장암의경우, bevacizumab 군과 cetuximab 군간유의한차이가없었다 (Fig. 2) (Table 3). 2) 전체반응률 (Overall Response Rate, ORR) 동일한생물학적치료제를투여한환자군에서원발병소위치에따라 ORR을비교했을때, bevacizumab 투여군, cetuximab 투여군모두에서원발병소위치에따른 ORR은유의한차이가없었다 (Table 4). 마찬가지로각원발병소에서약제에따른 ORR을비교한결과에서도두약제간유의한 ORR 차이가없었다 (Table 4). - 12 -
김유진 : 전이성직결장암환자에서원발병소위치에따른 Cetuximab 과 Bevacizumab 의치료효과비교분석 atients withous progression (%) 100 Bevacizumab for left (B-L) Cetuximab for left (C-L) Bevacizumab for right (B-R) Cetuximab for right (C-R) Log-rank test, B-L vs B-R p=0.877 C-L vs C-R p=0.044 B-L vs C-L p=0.573 B-R vs C-R p=0.030 number at risk Bevacizumab for left Cetuximab for left Bevacizumab for right Cetuximab for right Time(years) 72 58 31 21 15 7 3 1 0 39 30 15 5 5 3 1 0 0 36 25 12 7 5 4 1 0 0 14 8 3 1 0 0 0 0 0 Fig. 2 Kaplan-Meier plot for time to progression and log-rank test Table 3 Association between primary tumor site and selected treatment type for time to progression Non-progression rogression HR* (95% CI) Treatment type Bevacizumab Left side 17 (23.6) 55 (76.4) 1 Right side 12 (33.3) 24 (66.7) 1.05 (0.64-1.67) 0.845 Cetuximab Left side 8 (20.5) 31 (79.5) 1 Right side 1 (7.1) 13 (92.9) 1.92 (0.98-3.60) 0.050 rimary tumor site Right side Bevacizumab 12 (33.3) 24 (66.7) 1 Cetuximab 1 (7.1) 13 (92.9) 2.08 (1.03-4.03) 0.036 Left side Bevacizumab 17 (23.6) 55 (76.4) 1 Cetuximab 8 (20.5) 31 (79.5) 1.14 (0.73-1.75) 0.569 HR*: hazard ratio - 13 -
JKSH, VOL.38, NO.1 (2021) Table 4 Association between primary tumor site and selected treatment type for overall response rate Non-ORR ORR OR* (95% CI) Treatment type Bevacizumab Left side 61 (88.4) 8 (11.6) 1 Right side 27 (90.0) 3 (10.0) 1.09 (0.31-4.68) 0.904 Cetuximab Left side 32 (88.9) 4 (11.1) 1 Right side 12 (92.3) 1 (7.7) 1.15 (0.19-12.35) 0.89 rimary tumor site Right side Bevacizumab 27 (90.0) 3 (10.0) 1 Cetuximab 12 (92.3) 1 (7.7) 1.06 (0.15-11.78) 0.956 Left side Bevacizumab 61 (88.4) 8 (11.6) 1 Cetuximab 32 (88.9) 4 (11.1) 1.00 (0.31-3.69) 0.998 OR*: odds ratio 고찰및결론전이성직결장암치료에서좌측직결장암환자들이우측직결장암환자들보다예후가좋으며, systemic treatment에대해보다개선된 OS, FS를보인다고알려져있다. 1)-3) 더나아가전이성직결장암에서대표적으로사용되는생물학적치료제인 bevacizumab과 cetuximab의약효와원발병소의위치간연관성에대한연구가최근활발하게이루어지고있으며, 이에본연구에서는국내전이성직결장암환자를대상으로원발부위에따른생물학적치료제의약효를 TT와 ORR을통해비교하였다. 환자는원발부위와약제의종류에따라 4개의군으로분류하였다. Bevacizumab 투여군은 FOL- FOX, FOLFIRI와병용하여진행하였고 cetuximab 투여군은 FOLFIRI와병용한환자만있었으며, 이는 2015-2016년도당시전이성직결장암에서고식적치료요법 1차로 FOLFOX와 cetuximab 의병용이보험급여로인정되지않았기때문으로사료된다. 각군별환자의기본특성을비교하였을때유의한차이를보이는항목은비교군별로상이하였다. Bevacizumab 환자군에서원발병소에따라나이 (right 64.4±9.5 vs left 59.8±11.0; p= 0.037) 와이전항암화학요법시행유무 (right 5 [13.9%] vs left 32 [44.4%]; p=0.002) 에서유의한차이를보였으며, 우측직결장암환자군에서는생물학적치료제종류에따라나이 (bevacizumab 64.4±9.5 vs cetuximab 57.9±8.9; p=0.031) 가, 좌측직결장암환자군에서는성별 (bevacizumab male 38 [52.8%] vs cetuximab male 29 [74.4%]; p=0.027) 이유의하게달랐다. 또한, 약제종류에따라 EGFR과 KRAS status에서유의한차이를보였는데이는 cetuximab이 EGFR(+), KRAS(-) 인환자의경우에만투여가능하기때문이다. 이와같이각군비교별유의한차이를보이는환자 - 14 -
김유진 : 전이성직결장암환자에서원발병소위치에따른 Cetuximab 과 Bevacizumab 의치료효과비교분석 특성이다상이하여이후 TT, ORR 분석시해당항목을보정하지못하고통계분석을한점은본연구의한계점으로생각된다. 각약제내에서원발병소위치에따른약효의차이를보면, bevacizumab 투여군의경우원발병소위치와무관하게약효를보인선행연구결과도있었으나 11),12) 우측직결장암에서더높은사망률을보인연구도있었다. 8) 본연구에서는 bevacizumab 투여군에서원발병소의위치에따른 TT, ORR의차이가없어 bevacizumab의약효는원발병소위치와무관하다는결과가도출되었다. 반면, cetuximab 투여군에서는기존연구결과 7),8) 와같이좌측직결장암일때우측직결장암인경우보다 TT가연장되어질병진행이늦어진경향을보였다 (HR=1.92; 95% CI: 0.98-3.60; p=0.050). 원발병소의위치에따라분석한결과에서는좌측직결장암인경우 bevacizumab과 cetuximab 두약물간에유의한약효차이가없었지만, 우측직결장암인경우에는기존연구결과 7)-10) 와같이 bevacizumab 군에서 cetuximab 군에비해 TT가유의하게개선되었다 (HR=2.08, 95% CI: 1.03-4.03; p=0.036). EGFR 양성, RAS 정상형인환자들내에서 bevacizumab과 cetuximab의효과를비교한기존연구결과를보면원발병소의위치별로더확연한차이를보여좌측직결장암환자에서는 cetuximab이, 우측직결장암환자에서는 bevacizumab이사망률, FS 측면에서더우월한효과를나타내었다. 7)- 10) 그러나, 실제임상현장에서는 EGFR 양성, RAS 정상형인경우원발병소의위치와무관하게 cetuximab을고식적치료요법 1차로사용하고있기때문에 bevacizumab 사용환자가없어이러한하위그룹분석은실시하지못하였다. ORR의경우선행연구결과와는다르게원발병소위치나약제에따라유의한차이가없었다. 그이유는기존연구가보통치료시작후 6개월시점에반응평가를실시한것과달리본연구에서는 1년시점의반응을치료효과로보았는데, 전이성직결장암의특성상 1년시점에는두군모두질환이진행된환자의수가많았기때문으로추정된다. 이렇게원발병소의위치에따라약효차이가나타나 는이유로아직명확하게밝혀진바는없지만, 직결장암원발병소의위치에따른분자유전학적인차이가그원인으로추정되고있다. 우측직결장암의경우예후가좋지않다고알려진 KRAS, BRAF 돌연변이와 MSI-H가더많이나타나는특징이있으며, 5),13),14) 좌측직결장암에서는 EGFR, ERBB2의발현율이높고 T53 gene mutation이더많이발견되었다. 6),15),16) 이러한영향으로인해원발병소의위치가우측인경우좌측보다불량한예후를보이며, anti-egfr monoclonal antibody 약제의효과가낮게나타난다고예상된다. 본연구는국내전이성직결장암환자를대상으로원발병소의위치와생물학적치료제의약효간의상관관계를조사한첫연구라는점에서의미를가진다. 그러나전자의무기록을바탕으로후향적으로연구가진행되어수술여부와같이결과에영향을줄수있는다른인자를제어하지못하였다는점은이번연구의한계점으로생각된다. 또한원발병소위치에따라직결장암을분류할때에기존해부학적인기준인횡행결장의 2/3 지점을특정할수없어횡행결장을전부우측직결장암으로분류한점은연구결과에영향을주는요인이되었을수있다. 마지막으로 BRAF, MSI와같은분자유전학적검사를시행한환자수가부족하여추가적인분자생물학적분석이어려웠으며, 향후원발병소에다른약효차이의명확한원인을밝히기위해우측과좌측전이성직결장암간의분자생물학적및유전학적인차이에대한추가적인연구가필요할것으로사료된다. 현재국내에서는전이성직결장암환자에서 bevacizumab은고식적치료요법 1차와 2차로보험급여가인정되고있는반면, cetuximab은 1차에만보험급여인정되고있어생물학적치료제선택시 molecular status가 EGFR(+), RAS(-) 인환자의경우 1차로 cetuximab을선택하는경향이있었다. 그러나본연구의결과를통해 molecular status 만을고려하기보다추가적으로원발병소의위치도고려하여향후보다나은치료지침을설정할수있을것으로기대된다. 결론적으로좌측직결장암일경우에는 cetuximab과 bevacizumab 중어떤약제라도투여가가능하지만 RAS 정상형인경우에는선행연구결과를 - 15 -
JKSH, VOL.38, NO.1 (2021) 바탕으로 cetuximab을우선고려할수있다. 반면, 우측직결장암에서는 RAS 정상형여부와관계없이 bevacizumab을우선추천해야할것으로사료된다. 참고문헌 1) Alfonso G, Garcia G, Gallego I et al. rognostic and predictive factors in metastasic colorectal cancer. J Clin Oncol. 2018;36(4):690. 2) Fotios L, Dongyun Y, Linda Y et al. rimary tumor location as a prognostic factor in metastatic colorectal cancer. JNCI. 2015;107(3):dju427. 3) rice TJ, Beeke C, Ullah S et al. Does the primary site of colorectal cancer impact outcomes for patients with metastatic disease? Cancer. 2015;121(6):830-5. 4) Stintzing S, Tejpar S, Gibbs et al. Understanding the role of primary tumor localisation in colorectal cancer treatment and outcomes. Eur J Cancer 2017; 84:60-80. 5) Tran B, Kopetz S, Tie J et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117(20):4623-32. 6) Missiaglia E, Jacobs B, D Ario G et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol. 2014;25 (10):1995-2001. 7) Tejpar S, Stintzing S, Ciardiello F et al. rognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol. 2017;3(2):194-201. 8) Aljehani MA, Morgan JW, Guthrie LA et al. Association of primary tumor site with mortality in patients receiving bevacizumab and cetuximab for metastatic colorectal cancer. JAMA Surg. 2018;153 (1):60-7. 9) Moretto R, Cremolini C, Rossini D et al. Location of primary tumor and benefit from anti-epidermal growth factor receptor monoclonal antibodies in patients with RAS and BRAF wild-type metastatic colorectal cancer. Oncologist. 2016;21 (8):988-94. 10) Venook A, Niedzwiecki D, Innocenti F et al. Impact of primary (1 o ) tumor location on overall survival (OS) and progression-free survival (FS) in patients (pts) with metastatic colorectal cancer (mcrc): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2016;34 (15):3504. 11) Wong HL, Lee B, Field K et al. Impact of primary tumor site on bevacizumab efficacy in metastatic colorectal cancer. Clin Colorectal Cancer. 2016;15(2) :9-15. 12) Boisen MK, Johansen JS, Dehlendorff C et al. rimary tumor location and bevacizumab effectiveness in patients with metastatic colorectal cancer. Ann Oncol. 2013;24(10):2554-9. 13) Nitsche U, Stögbauer F, Späth C et al. Right sided colon cancer as a distinct histopathological subtype with reduced prognosis. Dig Surg. 2016;33(2):157-63. 14) Sinicrope FA, Mahoney MR, Yoon HH et al. Analysis of molecular markers by anatomic tumor site in stage Ⅲ colon carcinomas from adjuvant chemotherapy trial NCCTG N0147 (alliance). Clin Cancer Res. 2015;21(23):5294-304. - 16 -
김유진 : 전이성직결장암환자에서원발병소위치에따른 Cetuximab 과 Bevacizumab 의치료효과비교분석 15) Missiaglia E, Jacobs B, D Ario G et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol. 2014;25(10):1995-2001. 16) Mouradov D, Sloggett C, Jorissen RN et al. Colorectal cancer cell lines are representive models of the main molecular subtypes of primary cancer. Cancer Res. 2014;74(12):3238-47. - 17 -