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1 DOI: /trd ISSN: (Print)/ (Online) Tuberc Respir Dis 2009;67: CopyrightC2009. The Korean Academy of Tuberculosis and Respiratory Diseases. All rights reserved. 재발성비소세포폐암에서 Pemetrexed 치료효과와 Thymidylate Synthase 발현의관계 전남대학교의과대학 1 내과학교실, 2 병리학교실, 3 전남대학교의생명인력사업단박철규 1, 김규식 1, 오인재 1, Tseden-Ish Manaljav 1,3, 최유덕 2, 권용수 1, 김유일 1, 임성철 1, 김영철 1 Original Article Efficacy of Pemetrexed in Relapsed Non-Small Cell Lung Cancer and Thymidylate Synthase Expression Choel-Kyu Park, M.D. 1, Kyu-Sik Kim, M.D. 1, In-Jae Oh, M.D. 1, Manaljav Tseden-Ish, M.D. 1,3, Yoo-Duk Choi, M.D. 2, Yong-Soo Kwon, M.D. 1, Yoo-Il Kim, M.D. 1, Sung-Chul Lim, M.D. 1, Young-Chul Kim, M.D. 1 Departments of 1 Internal Medicine, 2 Pathology, Chonnam National University Medical School, 3 The Brain Korea 21 Project, Center for Biomedical Human Resources at Chonnam National University, Gwangju, Korea Background: Pemetrexed, a multi-targeted antifolate has been used as a second line treatment against non-small cell lung cancer (NSCLC). We aimed to clarify the efficacy and survival according to line of treatment, histologic type, and expression of thymidylate synthase (TS). Methods: Ninety-eight patients were treated with pemetrexed as a second line treatment (n=43) or as an additional course of treatment (n=55). TS expression was studied with immunohistochemistry and graded as 0 to 3 based on the extent of expression. Results: The response rate (RR) in 98 subjects was 10.2% and the disease control rate (DCR=PR+SD) was 30.6%. RR and DCR were 12.7% and 32.7% in non-squamous cell carcinoma (NSQC) compared to 7.0% and 27.9% in squamous cell carcinoma (SQC) (p>.05). No significant differences in RR and DCR were observed between a second line group (4.7%, 20.9%) and a further line group (14.5%, 38.2%). A similar trend was observed in the 88 response evaluable subjects. TS was expressed in 28.6% (grade 1), 24.5% (grade 2) and 7.1% (grade 3), respectively, and it was not expressed in 39.8% of subjects. TS expression rate was significantly higher in the SQC (72.1%) compared to NSQC (50.9%, p=0.033). However, the efficacy of pemetrexed was not significantly different by the extent of TS expression. Conclusion: Pemetrexed showed efficacy, not only in a second-line setting, but also in further lines of treatment for NSCLC. The efficacy of pemetrexed tended to be higher in patients with NSQC compared to SQC. TS expression rate was significantly higher in SQC compared to NSQC. Key Words: Non-small-cell lung cancer, Pemetrexed, Thymidylate synthase 서 론 Address for correspondence: Young-Chul Kim, M.D. Lung and Esophageal Cancer Clinic, Chonnam National University Hwasun Hospital, 160, Ilsim-ri, Hwasun-eup, Hwasun-gun, Jeonnam , Korea Phone: , Fax: , kyc0923@chonnam.ac.kr Received: Jul. 10, 2009 Accepted: Aug. 25, 2009 비소세포폐암 (non-small cell lung cancer, NSCLC) 은진단당시수술이불가능한 IIIB-IV병기등진행된병기가많고 1, 이에대한주된치료는항암화학요법이라할수있어서, 여러항암제를이용한병합처방들이사용되고있으나치료의효과를예측하기어려워서보통무작위로선택하여사용하게된다. 현재비소세포폐암의 1차항암치료는일반적으로백금 191

2 CK Park et al: Efficacy of pemetrexed and thymidylate synthase expression 유도체 (platinum) 를기반으로한병합화학요법이사용되고있으며, 이는보존적치료 (best supportive care, BSC) 에비하여생존기간을연장시킨다 2. 그러나이러한 1차항암치료후대부분의폐암환자들에게는질환의재발또는진행과함께 2차치료가필요하게된다. 2차치료에사용되는여러약제중 Docetaxel 은무작위적 3상임상연구에서보존적치료에비해저명하게중간생존기간을연장시킨최초의약제이다 (7.0 개월 vs. 4.6개월 ) 3. 이후다표적 (multi-targeted) 항엽산제제인 Pemetrexed 가 Docetaxel (75 mg/m 2 ) 과비교하여동등한효과를보이면서보다나은안전성을가지고있는것으로보고되었다 4. 2차치료에실패한비소세포폐암환자의항암화학치료에대해서는 Gefitinib과 Erlotinib (Epidermal growth factor receptor, Tyrosine kinase inhibitor; EGFR -TKI) 을제외하고는정립된지침은없는상태이나, 많은환자에서실제로 3차및그이상의항암치료를시행받고있다 5,6. Pemetrexed 는악성중피종 (malignant mesothelioma) 에대한 1차치료제로써 Cisplatin 과의병합요법이승인되었으며 7, 진행성비소세포폐암의 2차치료제로써단독요법으로인정되고있다 4. Pemetrexed 는다른항암약제에비해독성이비교적낮은것으로보고되고있어서, 효과뿐만아니라안정성에있어서도인정받고있다 8. 또한최근편평세포암종 (squamous cell carcinoma, SQC) 에비해비편평세포암종 (non-squamous cell histology, NSQC), 특히샘암종에서그효능이우월한것으로보고되고있고, Pemetrexed 의표적이되는암세포내단백질인 Thymidylate synthase (TS) 의발현정도가적을수록좋은효과를보이는것으로보고되고있다 8,9. 이에 Pemetrexed 가 3차이상단계의치료에도효과적인약물이될것으로사료되나, 현재까지 3차이상단계에있어서의치료효과에대한연구결과는부족한실정이다. 본연구에서는 Pemetrexed 치료를받은비소세포폐암환자들을대상으로임상적인예측인자로서치료단계및조직형, 그리고분자생물학적예측인자로서표적단백인 TS의발현여부에따른 Pemetrexed 약제의효능및생존율의차이를알아보고자한다. 대상및방법 1. 대상환자 2006년 5월부터 2008년 1월까지전남대학교병원에서 1 차항암화학치료후재발혹은진행된비소세포폐암환자중 Pemetrexed 치료를받았으며폐암조직보관상태가 양호한총 98명에대해조사를실시하였다. 환자들은각각 2차치료 (n=43) 혹은 3차이상의치료단계 (n=55) 로 Pemetrexed를치료받았으며, 2009년 2월까지추적관찰정보를의무기록검색을통하여수집하였다. 2. 방법모든환자들은조직학적또는세포학적으로비소세포암종으로확진하였으며, 주로 IIIB-IV병기 (n=82) 로진행된병기에서진단되었다. 총 98명으로부터얻어진파라핀포매조직을이용하여 TS 단백발현을관찰하기위한면역조직화학염색을시행하였다 (1:50 희석, DAKO, Glostrup, Denmark). TS 발현정도는발현범위 (extent) 에따라등급 0 (0%), 등급 1 (<25%), 등급 2 (25 50%), 등급 3 (>50%) 까지 4단계로등급을나누었으며, 또한등급 0 을비발현군 (not expressed group) 과등급 1부터 3까지를발현군 (not-expressed group) 으로나누어임상적인예측인자들을서로비교하였다. Pemetrexed는매 21일마다 1회 500 mg/m 2 용량으로 10분간정주하였다. 엽산은대개 Pemetrexed 정주 1주전부터매일 1 mg 경구로투여하였고, 정주후 3주까지지속하였다. Vitamin B12는정주 1주전 1.5 mg 1회경구로투여하였고, 정주후 9주간격으로반복하였다. 치료는질병이진행하거나사망또는중한독성이발생할때까지시행하였고, 환자의의사 ( 意思 ) 및의료인의판단에따라중단여부를결정하였다. Pemetrexed 의효능은 2주기마다시행한전산화단층촬영결과를근거로 the Response Evaluation Criteria in Solid Tumor (RECIST) 에의거하여부분관해 (partial response, PR), 안정 (stable disease, SD), 그리고진행 (progressive disease, PD) 으로구분하였다 10. Pemetrexed를투여받은 98명의전체대상을 ITT (intention to treat) 군으로정의하였고, 사망또는추적소실등으로인해효능에대한평가가불가능한 (not evaluable, NE) 환자들을제외한 88명을 RE (response evaluable) 군으로구분하여통계량을산출하였다. 3. 자료분석치료에따른효과의예측인자로반응률 (response rate, RR) 과질병조절률 (disease control rate, DCR) 은교차분석및카이제곱방법으로검증하였다. 총생존기간 (overall survival, OS) 과무진행생존기간 (progression free survival, PFS) 은 Pemetrexed 를투여하기시작한날을기준으로 192

3 Tuberculosis and Respiratory Diseases Vol. 67. No. 3, Sep 산정하였고, Kaplan-Meier 방법으로검증하여각각치료단계및조직형, TS 발현여부에따라비교하였다. 통계학적분석은 SPSS 15.0 (SPSS Inc., Chicago, IL, USA) 을사용하여시행하였고, 통계학적유의성은 0.05 이하로정의하였다. (n=52, 53.1%) 이다수를차지하고있었다. 53명의환자에서 IV 병기 (54.1%) 로진단받았으며, 29명 (29.6%) 은 IIIB 병기, 그리고 16명 (16.3%) 은진행성병기 (IIIB-IV) 이외의병기인 IB, IIIA로진단되어치료하였으나재발된경우들이었다. 결 과 2. 반응률및질병조절률 1. 환자의특성및분포 Pemetrexed 로치료받은총 98명에대해조사된기본적인환자및질병에대한특성은 Table 1에정리하였다. Pemetrexed 치료전평균항암치료의차수 (lines) 는 2.0차이었으며, 56.1% (n=55) 에서 3차이상의항암치료로써 Pemetrexed 를투여받았다. 전체환자의나이중앙값은 62.0세 (35 84세) 이었고, 성별에있어서는남성 (n=76, 77.6%) 의비율이높았으며, 비흡연자는 20명 (20.4%) 으로흡연자 (n=78, 79.6%) 의비율이높았다. 조직형에있어서는편평세포암종 (n=43, 43.9%) 보다비편평세포암종 (n= 55, 56.1%) 이다수를차지하고있었으며, 이중샘암종 98명전체대상 (ITT) 중 Pemetrexed 치료후 PR은 10 명, SD는 20명, 그리고 PD는 58명으로관찰되었고, 나머지 10명은사망 (n=5), 타요양기관전원 (n=5) 등으로추적소실되어평가가불가능하였다 (NE). 따라서 ITT군에서 RR은 10.2%, DCR은 30.6% 이었고, RE군에서는각각 11.4% 및 34.1% 를보였다 (Table 1). 조직형에따라분류하였을때, RR과 DCR은전체비소세포암종중편평세포암종 (7.0%, 27.9%) 에비해비편평세포암종 (12.7%, 32.7%) 에서높은경향을보였으나통계학적유의성은없었다 (Table 2). Pemetrexed 를투여한차수에따라분류하였을때, RR 은 2차투여군에서 4.7%, 3차이상투여군에서 14.5% 로 Table 1. Characteristics of patients and efficacy to pemetrexed Chracteristics Number of patients % Lines of treatment 2nd line 43 (43.9) 3rd or further line 55 (56.1) Sex (male/female) 76 (77.6)/22 (22.4) Smoking status Never-smoker 20 (20.4) Ever-smoker 78 (79.6) Histologic type Non-squamous cell ca 55 (56.1) ADC* 52 (53.1) Others 3 (3.1) Squamous cell ca 43 (43.9) Stage of disease IV 53 (54.1) IIIB 29 (29.6) IB, IIIA 16 (16.3) Response to treatment ITT RE ITT RE Disease control rate (DCR) (30.6) (34.1) Partial response (PR) (10.2) (11.4) Stable disease (SD) (20.4) (22.7) Progressive disease (PD) (59.2) (65.9) Not evaluable (NE) 10 - (10.2) - *Adenocarcinoma, Include large cell carcinoma, bronchoalveolar carcinoma, and etc., Intention to treatment population, Response evaluable population. 193

CK Park et al: Efficacy of pemetrexed and thymidylate synthase expression Table 2.

(7.0) 12 (27.9) 43 Lines of treatment (number/%) NSQC 2nd RE ITT RE 3 (7.9) 13 (31.6) 38 7 (12.7) 18 (32.7) 55 7 (14.0) 18 (36.0) 50 ITT 2 (4.7) 9 (20.

*Disease control=partial response Stable disease, Squamous cell carcinoma, Non-squamous cell carcinoma, Intention to treat ment population, Response evaluable

1%). 100; Primary antibody: DAKO, Denmark, dilution 1 50. 높은 경향을 보였으며(p=0.178), DCR은 2차 투여군 (20.9%)보다 3차 이상 투여군(38.2%)에서 높은 경향을 보였으나 유의한 차이는 보이지 않았다(p=0.

4 CK Park et al: Efficacy of pemetrexed and thymidylate synthase expression Table 2. Efficacy of pemetrexed according to histologic types and lines of treatment Histologic types (number/%) SQC Response ITT Partial response Disease control* Total 3 (7.0) 12 (27.9) 43 Lines of treatment (number/%) NSQC 2nd RE ITT RE 3 (7.9) 13 (31.6) 38 7 (12.7) 18 (32.7) 55 7 (14.0) 18 (36.0) 50 ITT 2 (4.7) 9 (20.9) 43 3rd or further RE ITT RE 2 (5.3) 9 (23.7) 38 8 (14.5) 21 (38.2) 55 8 (16.0) 21 (42.0) 50 All the data did not show significant differences (p 0.05). *Disease control=partial response Stable disease, Squamous cell carcinoma, Non-squamous cell carcinoma, Intention to treat ment population, Response evaluable population. Figure 1. Thymidylate synthase expression by immunohistochemical stain. (A) Grade 0 (39.8%), (B) Grade 1 (28.6%), (C) Grade 2 (24.5%), (D) Grade 3 (7.1%). 100; Primary antibody: DAKO, Denmark, dilution 높은 경향을 보였으며(p=0.178), DCR은 2차 투여군 (20.9%)보다 3차 이상 투여군(38.2%)에서 높은 경향을 보였으나 유의한 차이는 보이지 않았다(p=0.066) (Table 2). 이상의 ITT군에서의 성적과 같이 RE군에서도 조직형 과 투여 차수에 따른 유의한 차이는 관찰되지 않았다 (Table 1, 2) Thymidylate synthase 발현 여부에 따른 결과 분석 폐암조직 보관상태가 양호한 98명의 암조직에서 얻어 진 TS의 발현율은 각각 28.6% (등급 1), 24.5% (등급 2), 7.1% (등급 3)로 총 59명(60.2%)이었으며, 39명(39.8%)에 서는 발현되지 않았다(Figure 1). TS 발현율은 편평세포암

5 Tuberculosis and Respiratory Diseases Vol. 67. No. 3, Sep Table 3. Thymidylate synthase expression and correlation with histologic types and efficacy to pemetrexed Thymidylate synthase expression (number/%) Not expressed Expressed Total Histologic type SQC 12 (27.9) 31 (72.1)* 43 NSQC 27 (49.1) 28 (50.9) 55 Total 39 (39.8) 59 (60.2) 98 (100.0) Response ITT RE ITT RE ITT RE Partial response 5 (12.8) 5 (14.7) 5 (8.5) 5 (9.3) Disease control 14 (35.9) 14 (41.2) 16 (27.1) 16 (29.6) Total 39 (39.8) 34 (38.6) 59 (60.2) 54 (61.4) 98 (100) 88 (100) *p<0.05, Squamous cell carcinoma, Non-squamous cell histology, Disease control=partial response+stable disease, Intention to treatment population, Response evaluable population. Table 4. Overall survival (OS) and progression free survival (PFS) according to histologic type, lines of treatment and expression of thymidylate synthase (TS) Median 95% Significance survival Confidence (p-value) (months) interval (months) OS Histologic type SQC* NSQC Lines of treatment 2nd rd or further TS expression Not expresssed Expressed PFS Histologic type SQC* NSQC Lines of treatment 2nd rd or further TS expression Not expressed Expressed *Squamous cell carcinoma, Non-squamous cell histology. 종 (72.1%) 에서비편평세포암종 (50.9%) 에서보다유의하게높은발현율을보였다 (p=0.033). Pemetrexed의치료효과에대한척도로서 RR과 DCR에있어서는 TS 발현율 에따라유의한차이는보이지않았으며 (), RE군에서도유사한경향을보였다 (Table 3). 4. 생존율및무진행생존기간 OS 중앙값은 10.2개월 (95% CI 개월, 53.1% censoring) 이었으며, PFS 중앙값은 1.6개월 (95% CI 개월, 12.2% censoring) 이었다. OS는조직형에따른분류에서비편평세포암종 (12.4, 개월 ) 과편평세포암종 (12.1, 개월 ) 에서유의한차이는보이지않았다. 또한항암치료약제군에따른분류 (2차및 3차이상 ) 와 TS 발현여부에따른분류에있어서도차이는보이지않았다. PFS 역시조직형, 항암치료약제군및 TS 발현여부등에따른분류에있어의의있는차이는보이지않았다 (Table 4). 고찰진행된병기 (IIIB 또는 IV) 의비소세포폐암에서백금유도체 (Cisplatin or Carboplatin) 와 Gemcitabine, Vinorelbine, Taxanes (Paclitaxel or Docetaxel) 의 2제병합요법이일차적인항암화학치료처방으로사용된다 11. 이러한각각의 2제병합요법약제들은비교적동등한효능을가지고있으나독성에있어서는약제마다차이를보이고있다 12. Pemetrexed 는진행성비소세포폐암의 2차치료제로서단독요법으로사용되기시작하였다 4. 이후한 3상임상연 195

6 CK Park et al: Efficacy of pemetrexed and thymidylate synthase expression 구에서진행된비소세포폐암의 1차치료로써 Pemetrexed +Cisplatin과 Gemcitabine+Cisplatin 을비교한결과 Pemetrexed+Cisplatin군에서 Gemcitabine+Cisplatin군과비교하여유사한효능을보이면서도낮은독성을보였다. 또한조직형에따른효과를볼때 Pemetrexed+Cisplatin 을사용한경우편평세포암종에비해샘암종, 대세포암종에서보다우월한생존기간의연장을관찰할수있었다 8. 많은새로운항암제들이폐암치료에사용되지만, 2차항암치료에대한반응률은일반적으로 10% 미만으로보고되고있으며 13, Pemetrexed 에있어서도 1차치료에비해떨어지는것으로보고되고있다 4,14. 본연구에서는반응률및질병조절률이현재까지서양인들을대상으로한전향적연구들의결과와비교하여더높은경향을보였다. 그러나이는일반적으로동양인에서항암치료에대한효능이더높게보고되는점과, 본연구가후향적조사인관계로효능이낮아탈락된증례들이포함되지않은이유때문으로판단된다. 2차항암치료에실패한환자에서추가적인항암치료의역할에대해서는논쟁의여지가남아있으나 15,16, 최근한연구에서 2차항암치료에실패한환자를대상으로 3차항암치료에있어 Pemetrexed 를사용한경우에도치료반응에있어의의있는효능을보였고, 약제독성이낮아서순응도가높은것으로보고되었다 17. 이에본연구에서는조직형들간의차이및 2차투여군과 3차이상의투여군, 즉투여차수에따른 Pemetrexed 의치료효과를비교하였다. 우선, 조직형들간의비교에있어서는통계학적유의성은확인할수없었으나편평세포암종에비해비편평세포암종에서우월한경향을관찰할수있었다. 투여차수에따라비교하였을때, 2차투여군에비해 3차이상의투여군에있어높은경향을보였으나유의한차이를보이지않았으며, 이는 3차이상의치료에서도 2차치료와마찬가지로동등한치료효과를보이는것으로판단된다. OS 및 PFS에있어서도조직형및투여차수에따른차이가있을것으로생각하였으나본연구에서는유의한차이를보이지않았다. 이는후향적인분석으로비교적긴추적관찰기간 (13개월) 을가졌었고, 다수에서 4차이상의항암치료를받으면서추적기간이연장되었던것이영향을끼친것으로생각할수있겠으며, 추후전향적인연구를통하여검증할필요가있겠다. TS는 deoxyuridine 5'-monophosphate (dump) 를 DNA 합성에필수적인 4가지 deoxynucleoside triphosphate 중하나인 thymidine 5'-triphosphate (TTP) 의전구 체인 thymidine 5'-monophos-phate로전환하는역할을한다. TS에대한길항작용은 DNA 합성과세포증식을억제하기때문에이효소는항암화학치료약제의중요한표적이될수있다 18. 대표적인 TS 길항제로서 5-Fluorouracil (5-FU) 와 5-Fluoro- deoxyuridine (5-FUdR) 이있으며, 현재대장직장암및기타암에대한치료제로사용되고있다 19. 따라서 TS는세포증식에대한유용한표지자로 20, 여러암종에서예후를예측할수있는분자수준의표지자로연구되고있으며, 실제대장직장암, 위암, 유방암, 난소암에서고농도의 TS 단백질발현이생존기간및 5-FU에대한부정적인반응과관련됨이보고되고있다 21,22. 또한 Pemetrexed 의항암제감수성에대해치료기전과관련된유전자발현율의차이를관찰한한연구에서는치료의표적이되는 TS, Dihydrofolate reductase (DHFR), Glycinamide ribonucleo-tide formyl transferase (GARFT) 의유전자발현정도와치료효과간에상관관계가있음이관찰되었다 23. 또한비소세포폐암세포를이용한연구에서암세포의높은증식활성과 TS 단백질의발현이유의한관련성이있고그결과높은 TS 수치를보이는비소세포폐암환자에서불량한예후를가질수있다는보고가있었다 9. 특히한연구에서는저자의연구결과에서와같이 TS가샘암종에서보다편평세포암종에서높은발현율을보였으며, 또한악성도가높은암종에서보다높게발현되었다 24. 이에본연구에서는 TS에대한일차항체를이용하여 Pemetrexed 치료전환자의조직을면역조직화학염색을함으로써치료효과에대한예측인자로서의의의를알아보고자하였다. 그결과편평세포암종에서비편평세포암종보다 TS의발현율이의의있게높았고, 또한 Pemetrexed 치료후편평세포암종보다비편평세포암종에서질병조절률이높은경향을보여, 이를근거로하여유추해볼때비편평세포암종에서더나은치료효과를예측해볼수있었으나 RR, DCR, 총 OS 및 PFS에있어서유의한차이는관찰되지않았다. TS 발현정도에따라등급별 (grade 0 3) 로비교해보았으나이에따른유의한임상상의차이는발견되지않았다. 그러나이는전체비소세포폐암환자중 Pemetrexed 로치료받은, 조직보관상태가양호한 98명의환자에서만면역조직화학염색을시행한결과로, 향후에는 Pemetrexed 를투여하는가능한많은환자들의조직검체를이용한추가적인연구가필요할것으로생각한다. 196

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기관고유연구사업결과보고 작성요령 2001 ~ 2004 2005 ~ 2007 2008 ~ 2010 2001 ~ 2004 2005 ~ 2007 2008 ~ 2010 1 2/3 2 1 0 2 3 52 0 31 83 12 6 3 21 593 404 304 1,301 4 3 1 8 159 191 116 466 6 11 (`1: (1: 16 33 44 106